Rachel Litman Flynn, Ph.D.
Ph.D.: University of Massachusetts Medical School
Post-Doctoral Fellow: Harvard Medical School, Massachusetts General Hospital Cancer Center
The focus of the Laboratory of Genomic Instability and Cancer Therapeutics is to understand the mechanisms regulating mammalian telomere maintenance and to understand how defects in this process contribute to premature aging and cancer progression. The hope is that these studies will allow us to gain the mechanistic insight necessary to define novel targets and/or strategies in the treatment of human disease.
In my lab we use a combination of biochemical and cell biological approaches to study the function of mammalian telomeres. Telomeres cap the ends of linear chromosomes and provide a molecular barrier for the human genome. Following each cell division, progressive telomere shortening erodes that barrier and compromises the stability of the genome. Critically short, or dysfunctional telomeres induce replicative senescence and/or cell death and ultimately, lead to cellular aging. Cancer cells, however, overcome the replicative senescence associated with critically short telomeres by exploiting mechanisms of telomere elongation. Reactivation of the enzyme telomerase or activation of the Alternative Lengthening of Telomeres (ALT) pathway accounts for cellular immortalization in the majority of all human cancers. Clinical trials are currently underway to test the efficacy of telomerase inhibitors in the treatment of telomerase-positive cancers; however, there are no known treatments for ALT-positive cancers. By gaining a better mechanistic understanding of how normal telomeres are maintained, and how dysfunctional telomeres bypass replicative senescence, we hope to identify novel therapeutic approaches in the treatment of both premature aging syndromes and cancer.
- September 1, 2014: Dr. Flynn was awarded the Peter Paul Professorship Award
- August 13, 2014: Dr. Rachel Flynn receives Award for Foster Foundation
Floro J, Dai A, Metzger A, Mora-Martin A, Ganem NJ, Cifuentes D, Wu CS, Dalal J, Lyons SM, Labadorf A, Flynn RL. SDE2 is an essential gene required for ribosome biogenesis and the regulation of alternative splicing. Nucleic Acids Res. 2021 Aug 07. PMID: 34365507
Mason-Osann E, Terranova K, Lupo N, Lock YJ, Carson LM, Flynn RL. RAD54 promotes alternative lengthening of telomeres by mediating branch migration. EMBO Rep. 2020 06 04; 21(6):e49495. PMID: 32337843; PMCID: PMC7271314; DOI: 10.15252/embr.201949495;
Flynn RL, Heaphy CM. Surviving Telomere Attrition with the MiDAS Touch. Trends Genet. 2019 11; 35(11):783-785. PMID: 31526614
Panier S, Maric M, Hewitt G, Mason-Osann E, Gali H, Dai A, Labadorf A, Guervilly JH, Ruis P, Segura-Bayona S, Belan O, Marzec P, Gaillard PHL, Flynn RL, Boulton SJ. SLX4IP Antagonizes Promiscuous BLM Activity during ALT Maintenance. Mol Cell. 2019 10 03; 76(1):27-43.e11. PMID: 31447390; PMCID: PMC6863466; DOI: 10.1016/j.molcel.2019.07.010;
Mason-Osann E, Gali H, Flynn RL. Resolving Roadblocks to Telomere Replication. Methods Mol Biol. 2019; 1999:31-57. PMID: 31127568
Gali H, Mason-Osann E, Flynn RL. Direct Visualization of DNA Replication at Telomeres Using DNA Fiber Combing Combined with Telomere FISH. Methods Mol Biol. 2019; 1999:319-325. PMID: 31127588
Mason-Osann E, Dai A, Floro J, Lock YJ, Reiss M, Gali H, Matschulat A, Labadorf A, Flynn RL. Identification of a novel gene fusion in ALT positive osteosarcoma. Oncotarget. 2018 Aug 28; 9(67):32868-32880. PMID: 30214690; PMCID: PMC6132345; DOI: 10.18632/oncotarget.26029;
Cox KE, Maréchal A, Flynn RL. SMARCAL1 Resolves Replication Stress at ALT Telomeres. Cell Rep. 2016 Feb 9; 14(5):1032-40. PMID: 26832416; PMCID: PMC5051350; DOI: 10.1016/j.celrep.2016.01.011;
Flynn RL, Cox KE, Jeitany M, Wakimoto H, Bryll AR, Ganem NJ, Bersani F, Pineda JR, Suvà ML, Benes CH, Haber DA, Boussin FD, Zou L. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science. 2015 Jan 16; 347(6219):273-7. PMID: 25593184; PMCID: PMC4358324; DOI: 10.1126/science.1257216;
Flynn RL, Cox KE, Jeitany M, Wakimoto H, Bryll AR, Ganem NJ, Bersani F, Pineda JR, Suvà ML, Benes CH, Haber DA, Boussin FD, Zou L. Alternative Lengthening of Telomeres Renders Cancer Cells Hypersensitive to ATR Inhibitors. Science. 2015 Jan 16;347(6219):273-7. PMID: 25593184
Flynn RL, Centore RC, O’Sullivan RJ, Rai R, Tse A, Songyang Z, Chang S, Karlseder J, Zou L. TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA. Nature. 2011 Mar 24;471 (7339):532-6. PMID: 21399625. PMC:3078637 .
Centore RC, Havens CG, Manning AL, Li JM, Flynn RL,Tse A, Jin J, Dyson NJ, Walter JC, Zou L. CRL4(Cdt2)-mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase. Mol Cell. 2010 Oct 8;40(1):22-33. PMID: 20932472. .
Xie J, *Flynn RL,Wang S, Peng M, Guillemette S, Rooney T, Cantor SB. Targeting the FANCJ-BRCA1 interaction promotes a switch from recombination to poleta-dependent bypass. Oncogene. 2010 Apr 29;29(17):2499-508. PMID: 20173781/PMC2909592*co-first author.
Peng M, *Litman R, Xie J, Sharma S, Brosh RM Jr, Cantor SB. The FANCJ/MutLalpha interaction is required for correction of the cross-link response in FA-J cells. EMBO J. 2007 Jul 11;26(13):3238-49. PMID: 17581638. *Co-First Author
Litman R, Peng M, Jin Z, Zhang F, Zhang J, Powell S, Andreassen PR, Cantor SB. BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell. 2005 Sep;8(3):255-65. PMID: 16153896.
Office:The Cancer Center, Boston University School of Medicine, 72 East Concord Street, K-712D, Boston, MA 02118