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Nicholas R Rhind PhD

TitleProfessor
InstitutionUniversity of Massachusetts Medical School
DepartmentBiochemistry and Molecular Pharmacology
AddressUniversity of Massachusetts Medical School
364 Plantation Street, LRB
Worcester MA 01605
Phone508-856-8316
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    Other Positions
    InstitutionUMMS - School of Medicine
    DepartmentBiochemistry and Molecular Pharmacology

    InstitutionUMMS - School of Medicine
    DepartmentRadiology

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentBiochemistry and Molecular Pharmacology

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentBioinformatics and Computational Biology

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentCell Biology

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentInterdisciplinary Graduate Program

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentMD/PhD Program

    InstitutionUMMS - Programs, Centers and Institutes
    DepartmentBioinformatics and Integrative Biology


    Collapse Biography 
    Collapse education and training
    Brown University, Providence, RI, United StatesB SCMathematics
    Brown University, Providence, RI, United StatesBABiology
    University of California, Berkeley, Berkeley, CA, United StatesPHDMolecular & Cell Biology

    Collapse Overview 
    Collapse overview


    Lab Website



    Academic Background



    Nick Rhind received his Ph.D. from the Department of Molecular and Cell Biology at U.C. Berkeley in 1995, where he studied worm sex determination with Barbara Meyer. He was a Leukemia and Lymphoma Society post-doctoral fellow with Paul Russell at the Scripps Research Institute from 1996 to 2001.



    Regulation of DNA Replication



    Photo: Nick Rhind



    Amajor current interest of my lab is how replication is regulated during S phase. We are interested both in how normal S phase is organized to insure efficient replication of the entire genome, and how cells respond to DNA damage during S phase to coordinate replication and repair.



    Most of the work in my lab focuses on the fission yeast Schizosaccharomyces pombe (Figure 1). Fission yeast is a great organism for studying replication because it has a simple, well-understood cell cycle and is amenable to genetic, molecular and biochemical approaches. It has the added attraction that the mechanisms of cell cycle and checkpoint control in fission yeast are very similar to those used by human cells. In fact, much of what is known about human cell cycle and checkpoints was first discovered in yeast. My lab is currently pursuing two general areas of the regulation of replication.



    Regulation of Origin Firing Kinetics



    Eukaryotic genomes replicate in defined patterns, with some parts of the genome replicating early in S phase and other parts replicating later. Replication timing correlates with transcription, chromatin modification, sub-nuclear localization and genome evolution, suggesting an intimate association between replication timing and other important aspects of chromosome metabolism. However, the mechanism of replication timing is currently unknown.



    We developed an computational approach to extract replication kinetics from genome-wide replication timecourses (Figure 2). Our results support a model where earlier-firing origins have more MCM complexes loaded and a more-accessible chromatin environment (Figure 3). The MCM complex is the replicative helicase; its loading is what establishes sites as potential replication origins. We propose that the timing of origin firing is regulated in by the number of MCM complexes loaded at an origin. Thus, for the first time, our model suggests a detailed, testable, biochemically plausible mechanism for the regulation of replication timing in eukaryotes. ChIP-seq validation of our model confirms that early firing origins have more MCM loaded. We are currently exploring how MCM loading is regulated at different origins.



    Checkpoint Regulation of Replication



    Checkpoints are mechanisms that cells use to deal with problems during the cell cycle, such as DNA damage, replication errors and misattachment of chromosomes to the mitotic spindle. By actively responding to these problems, cells can fix most of them. In contrast, cells that lack proper checkpoints are very sensitive to DNA damage and show increased rates of mutation and other chromosomal abnormalities. Loss of checkpoints is an important step in the development of cancer.



    The S-phase DNA damage checkpoint slows the rate of replication in response to DNA damage. The simple model is that this checkpoint prevents damaged DNA from being replicated before it is repaired. However, the checkpoint is clearly more subtle than that. Recent results from yeast and human cells suggest that this checkpoint coordinates recombinational repair and replication during S-phase. In particular, we have established an epistatic pathway of recombinational-repair proteins that regulate replication-fork progress in response to DNA damage. We think this pathway regulates a choice the fork makes when it encounters damage: it can replicate quickly in an error-prone manner or, via a checkpoint-dependant mechanism, it can use recombinational strand switching to replicate the damaged template accurately, but slowly (Figure 4). Furthermore, via phospho-proteomics, we have identified candidate checkpoint targets, which maybe responsible for making this decision.



     



     



     



     



     



    Figures





     


     


    Fission Yeast


     


    Figure 1.Fission Yeast

    The fission yeast Schizosaccharomyces pombeis a simple, single-cell eukaryote that has proven to be an excellent model for cell cycle and checkpoint regulation. It divides by medial fission, distinguishing it from the budding yeast Saccharomyces cerevisiae, another popular lab yeast.


     


     


    Measuring Replication Kinetics



    Figure 2. Measuring Replication Kinetics

    A) Using deep sequencing to assay the change from one copy to two copies during replication, we can create replication profiles in which each origin is a peaks. Shown is the replication profile for Chromosome 3. The blue dots represent the computer-identified location and height of the origin peaks.



    B) A expanded view of the well-studied left arm of Chromosome 3. The green bars represent confirmed origins in the region. The numbered origins were previously described. We have confirmed the activity of the two unnumbered origins by single-molecule DNA fiber origin mapping.



    C) Using replication profile timecourses, we can study replication kinetics The extent of replication is determined at timepoints throughout S phase and plotted along the chromosome; for clarity, only 4 time points are show here. Peaks in the profiles (a, b and c) correspond to origins; the slope of the curve leading away from each peak is affected by fork velocity. Fork pause site are recognized as very steep curves that are only replicated by forks coming from the other direction. The individual profiles are assembled into a kinetic profile that reveals the dynamics of replication over time. In particular, the kinetics of origin firing distinguish early efficient origins (a) from early inefficient origins (b) and late efficient origins (c).



     



    A Model for the Regulation of Replication Timing



    Figure 3. A Model for the Regulation of Replication Timing

    We propose that the timing of origin firing is regulated by the number of MCMs loaded. Origins at which many MCMs are loaded are more likely to fire in early S and therefore have an early average firing time; origins at which fewer MCMs are loaded are less likely to fire in early S and therefore have a later average firing time. We further propose that the number of MCMs loaded is regulated by the affinity of ORC for the origin. High-affinity origins are bound by ORC for more of G1 and thus have more MCMs loaded. Heterochromatin could provide a second layer of regulation, on top of our proposed MCM-based mechanism. Heterochromatin could delay origin firing by inhibiting any step in MCM loading or activation. However, based on our preliminary results that many MCMs are loaded at late-firing heterochromatic subtelomeric origins, we propose that heterochromatin acts mainly to inhibit MCM activation.



     



    A Model for Checkpoint Regulation of Replication



     



    Figure 4. A Model for Checkpoint Regulation of Replication

    We have identified three classes of proteins required for the S-phase DNA damage checkpoint, which we think are involved in a checkpoint-dependent choice between slow and fast replication through DNA damage. Mus81 and other fork-metabolism proteins are required for Cds1-dependent checkpoint slowing of replication forks, presumably by recombinational template switching. Rad51 and other recombination protein antagonize the Mus81-dependent pathway and allow fast replication, possibly by leading-strand repriming. Sfr1, Rqh1 and other recombination regulator inhibit the Rad51-dependent pathway and allow the Mus81-dependent pathway to function.



     





     



     


    Collapse Rotation Projects

    Potential Rotation Projects

    1) Coordination of replication and recombination by the S-phase DNA damage checkpoint

    The replication checkpoint coordinates replication and recombinational repair to allow for the replication of damaged templates, however the mechanism by which the checkpoint regulates recombination is unknown. We have identified a number of potential checkpoint-kinase targets by phosphoproteomics. One possible rotation project would be to create site-directed mutations that would prevent kinase regulation of one or more of the targets. These mutations could be used to validate the role of the target in the checkpoint and to test the importance of checkpoint regulation in S-phase DNA repair.

    2) Regulation of replication timing

    Heterochromatin regulates the timing of replication origin firing, however the mechanism by which it affects origin function is unknown. We have developed a model of how origin timing is regulated in non-heterochromatic chromatin; now we want to test how heterochromatin affects this mechanism. In particular, we want to manipulate the heterochromatic context at specific loci, measure the changes in origin timing and investigate the molecular mechanisms responsible for the change. One possible rotation project would be to establish heterochromatin at a well-characterized origin, measure origin timing, which we presume will be delayed, and then test at which step origin firing is delayed.




    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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    1. Chen W, Moore J, Ozadam H, Shulha HP, Rhind N, Weng Z, Moore MJ. Transcriptome-wide Interrogation of the Functional Intronome by Spliceosome Profiling. Cell. 2018 May 03; 173(4):1031-1044.e13. PMID: 29727662.
      View in: PubMed
    2. Rhind N. Cell Size Control via an Unstable Accumulating Activator and the Phenomenon of Excess Mitotic Delay. Bioessays. 2018 Feb; 40(2). PMID: 29283187.
      View in: PubMed
    3. Iyer DR, Rhind N. Replication fork slowing and stalling are distinct, checkpoint-independent consequences of replicating damaged DNA. PLoS Genet. 2017 Aug; 13(8):e1006958. PMID: 28806726.
      View in: PubMed
    4. Santaguida S, Richardson A, Iyer DR, M'Saad O, Zasadil L, Knouse KA, Wong YL, Rhind N, Desai A, Amon A. Chromosome Mis-segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes that Are Eliminated by the Immune System. Dev Cell. 2017 Jun 19; 41(6):638-651.e5. PMID: 28633018.
      View in: PubMed
    5. Hwang Y, Futran M, Hidalgo D, Pop R, Iyer DR, Scully R, Rhind N, Socolovsky M. Global increase in replication fork speed during a p57KIP2-regulated erythroid cell fate switch. Sci Adv. 2017 May; 3(5):e1700298. PMID: 28560351.
      View in: PubMed
    6. Keifenheim D, Sun XM, D'Souza E, Ohira MJ, Magner M, Mayhew MB, Marguerat S, Rhind N. Size-Dependent Expression of the Mitotic Activator Cdc25 Suggests a Mechanism of Size Control in Fission Yeast. Curr Biol. 2017 Apr 29. PMID: 28479325.
      View in: PubMed
    7. Ohira MJ, Hendrickson DG, McIsaac RS, Rhind N. An Estradiol-Inducible Promoter Enables Fast, Graduated Control of Gene Expression in Fission Yeast. Yeast. 2017 Apr 19. PMID: 28423198.
      View in: PubMed
    8. Iyer DR, Rhind N. The Intra-S Checkpoint Responses to DNA Damage. Genes (Basel). 2017 Feb 17; 8(2). PMID: 28218681.
      View in: PubMed
    9. Das SP, Borrman T, Liu VW, Yang SC, Bechhoefer J, Rhind N. Corrigendum: Replication timing is regulated by the number of MCMs loaded at origins. Genome Res. 2016 Dec; 26(12):1761. PMID: 27934699.
      View in: PubMed
    10. Chen JS, Beckley JR, Ren L, Feoktistova A, Jensen MA, Rhind N, Gould KL. Discovery of genes involved in mitosis, cell division, cell wall integrity and chromosome segregation through construction of Schizosaccharomyces pombe deletion strains. Yeast. 2016 Sep; 33(9):507-17. PMID: 27168121.
      View in: PubMed
    11. Willis NA, Zhou C, Elia AE, Murray JM, Carr AM, Elledge SJ, Rhind N. Identification of S-phase DNA damage-response targets in fission yeast reveals conservation of damage-response networks. Proc Natl Acad Sci U S A. 2016 Jun 28; 113(26):E3676-85. PMID: 27298342.
      View in: PubMed
    12. Das SP, Rhind N. How and why multiple MCMs are loaded at origins of DNA replication. Bioessays. 2016 Jul; 38(7):613-7. PMID: 27174869.
      View in: PubMed
    13. Das SP, Borrman T, Liu VW, Yang SC, Bechhoefer J, Rhind N. Replication timing is regulated by the number of MCMs loaded at origins. Genome Res. 2015 Dec; 25(12):1886-92. PMID: 26359232.
      View in: PubMed
    14. Rhind N. Incorporation of thymidine analogs for studying replication kinetics in fission yeast. Methods Mol Biol. 2015; 1300:99-104. PMID: 25916707.
      View in: PubMed
    15. Rhind N. The three most important things about origins: location, location, location. Mol Syst Biol. 2014 Apr 04; 10:723. PMID: 24705498.
      View in: PubMed
    16. Iyer DR, Rhind N. Checkpoint regulation of replication forks: global or local? Biochem Soc Trans. 2013 Dec; 41(6):1701-5. PMID: 24256278.
      View in: PubMed
    17. Rhind N, Gilbert DM. DNA replication timing. Cold Spring Harb Perspect Biol. 2013 Aug 01; 5(8):a010132. PMID: 23838440.
      View in: PubMed
    18. Rhind N, Russell P. Signaling pathways that regulate cell division. Cold Spring Harb Perspect Biol. 2012 Oct 01; 4(10). PMID: 23028116.
      View in: PubMed
    19. Xu J, Yanagisawa Y, Tsankov AM, Hart C, Aoki K, Kommajosyula N, Steinmann KE, Bochicchio J, Russ C, Regev A, Rando OJ, Nusbaum C, Niki H, Milos P, Weng Z, Rhind N. Genome-wide identification and characterization of replication origins by deep sequencing. Genome Biol. 2012; 13(4):R27. PMID: 22531001.
      View in: PubMed
    20. Bechhoefer J, Rhind N. Replication timing and its emergence from stochastic processes. Trends Genet. 2012 Aug; 28(8):374-81. PMID: 22520729.
      View in: PubMed
    21. Tsankov A, Yanagisawa Y, Rhind N, Regev A, Rando OJ. Evolutionary divergence of intrinsic and trans-regulated nucleosome positioning sequences reveals plastic rules for chromatin organization. Genome Res. 2011 Nov; 21(11):1851-62. PMID: 21914852.
      View in: PubMed
    22. Grabherr MG, Haas BJ, Yassour M, Levin JZ, Thompson DA, Amit I, Adiconis X, Fan L, Raychowdhury R, Zeng Q, Chen Z, Mauceli E, Hacohen N, Gnirke A, Rhind N, di Palma F, Birren BW, Nusbaum C, Lindblad-Toh K, Friedman N, Regev A. Full-length transcriptome assembly from RNA-Seq data without a reference genome. Nat Biotechnol. 2011 May 15; 29(7):644-52. PMID: 21572440.
      View in: PubMed
    23. Rhind N, Chen Z, Yassour M, Thompson DA, Haas BJ, Habib N, Wapinski I, Roy S, Lin MF, Heiman DI, Young SK, Furuya K, Guo Y, Pidoux A, Chen HM, Robbertse B, Goldberg JM, Aoki K, Bayne EH, Berlin AM, Desjardins CA, Dobbs E, Dukaj L, Fan L, FitzGerald MG, French C, Gujja S, Hansen K, Keifenheim D, Levin JZ, Mosher RA, Müller CA, Pfiffner J, Priest M, Russ C, Smialowska A, Swoboda P, Sykes SM, Vaughn M, Vengrova S, Yoder R, Zeng Q, Allshire R, Baulcombe D, Birren BW, Brown W, Ekwall K, Kellis M, Leatherwood J, Levin H, Margalit H, Martienssen R, Nieduszynski CA, Spatafora JW, Friedman N, Dalgaard JZ, Baumann P, Niki H, Regev A, Nusbaum C. Comparative functional genomics of the fission yeasts. Science. 2011 May 20; 332(6032):930-6. PMID: 21511999.
      View in: PubMed
    24. Willis N, Rhind N. Studying G2 DNA damage checkpoints using the fission yeast Schizosaccharomyces pombe. Methods Mol Biol. 2011; 782:1-12. PMID: 21870280.
      View in: PubMed
    25. Willis N, Rhind N. Studying S-phase DNA damage checkpoints using the fission yeast Schizosaccharomyces pombe. Methods Mol Biol. 2011; 782:13-21. PMID: 21870281.
      View in: PubMed
    26. Limbo O, Porter-Goff ME, Rhind N, Russell P. Mre11 nuclease activity and Ctp1 regulate Chk1 activation by Rad3ATR and Tel1ATM checkpoint kinases at double-strand breaks. Mol Cell Biol. 2011 Feb; 31(3):573-83. PMID: 21098122.
      View in: PubMed
    27. Yang SC, Rhind N, Bechhoefer J. Modeling genome-wide replication kinetics reveals a mechanism for regulation of replication timing. Mol Syst Biol. 2010 Aug 24; 6:404. PMID: 20739926.
      View in: PubMed
    28. Willis N, Rhind N. The fission yeast Rad32(Mre11)-Rad50-Nbs1 complex acts both upstream and downstream of checkpoint signaling in the S-phase DNA damage checkpoint. Genetics. 2010 Apr; 184(4):887-97. PMID: 20065069.
      View in: PubMed
    29. Rhind N, Yang SC, Bechhoefer J. Reconciling stochastic origin firing with defined replication timing. Chromosome Res. 2010 Jan; 18(1):35-43. PMID: 20205352.
      View in: PubMed
    30. Dutta C, Rhind N. The role of specific checkpoint-induced S-phase transcripts in resistance to replicative stress. PLoS One. 2009 Sep 11; 4(9):e6944. PMID: 19750219.
      View in: PubMed
    31. Willis N, Rhind N. Regulation of DNA replication by the S-phase DNA damage checkpoint. Cell Div. 2009 Jul 03; 4:13. PMID: 19575778.
      View in: PubMed
    32. Rhind N. Changing of the guard: how ATM hands off DNA double-strand break signaling to ATR. Mol Cell. 2009 Mar 27; 33(6):672-4. PMID: 19328060.
      View in: PubMed
    33. Porter-Goff ME, Rhind N. The role of MRN in the S-phase DNA damage checkpoint is independent of its Ctp1-dependent roles in double-strand break repair and checkpoint signaling. Mol Biol Cell. 2009 Apr; 20(7):2096-107. PMID: 19211838.
      View in: PubMed
    34. Rhind N. Incorporation of thymidine analogs for studying replication kinetics in fission yeast. Methods Mol Biol. 2009; 521:509-15. PMID: 19563126.
      View in: PubMed
    35. Willis N, Rhind N. Mus81, Rhp51(Rad51), and Rqh1 form an epistatic pathway required for the S-phase DNA damage checkpoint. Mol Biol Cell. 2009 Feb; 20(3):819-33. PMID: 19037101.
      View in: PubMed
    36. Patel PK, Kommajosyula N, Rosebrock A, Bensimon A, Leatherwood J, Bechhoefer J, Rhind N. The Hsk1(Cdc7) replication kinase regulates origin efficiency. Mol Biol Cell. 2008 Dec; 19(12):5550-8. PMID: 18799612.
      View in: PubMed
    37. Rhind N. An intrinsic checkpoint model for regulation of replication origins. Cell Cycle. 2008 Sep 1; 7(17):2619-20. PMID: 18728394.
      View in: PubMed
    38. Dutta C, Patel PK, Rosebrock A, Oliva A, Leatherwood J, Rhind N. The DNA replication checkpoint directly regulates MBF-dependent G1/S transcription. Mol Cell Biol. 2008 Oct; 28(19):5977-85. PMID: 18662996.
      View in: PubMed
    39. Rhind N. DNA replication timing: random thoughts about origin firing. Nat Cell Biol. 2006 Dec; 8(12):1313-6. PMID: 17139278.
      View in: PubMed
    40. Kommajosyula N, Rhind N. Cdc2 tyrosine phosphorylation is not required for the S-phase DNA damage checkpoint in fission yeast. Cell Cycle. 2006 Nov 1; 5(21):2495-500. PMID: 17102632.
      View in: PubMed
    41. Forsburg SL, Rhind N. Basic methods for fission yeast. Yeast. 2006 Feb; 23(3):173-83. PMID: 16498704.
      View in: PubMed
    42. Patel PK, Arcangioli B, Baker SP, Bensimon A, Rhind N. DNA replication origins fire stochastically in fission yeast. Mol Biol Cell. 2006 Jan; 17(1):308-16. PMID: 16251353.
      View in: PubMed
    43. Sigova A, Rhind N, Zamore PD. A single Argonaute protein mediates both transcriptional and posttranscriptional silencing in Schizosaccharomyces pombe. Genes Dev. 2004 Oct 1; 18(19):2359-67. PMID: 15371329.
      View in: PubMed
    44. Sivakumar S, Porter-Goff M, Patel PK, Benoit K, Rhind N. In vivo labeling of fission yeast DNA with thymidine and thymidine analogs. Methods. 2004 Jul; 33(3):213-9. PMID: 15157888.
      View in: PubMed
    45. Chahwan C, Nakamura TM, Sivakumar S, Russell P, Rhind N. The fission yeast Rad32 (Mre11)-Rad50-Nbs1 complex is required for the S-phase DNA damage checkpoint. Mol Cell Biol. 2003 Sep; 23(18):6564-73. PMID: 12944482.
      View in: PubMed
    46. Rhind NR, Miller LM, Kopczynski JB, Meyer BJ. xol-1 acts as an early switch in the C. elegans male/hermaphrodite decision. Cell. 1995 Jan 13; 80(1):71-82. PMID: 7813020.
      View in: PubMed
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