Title | TIMELESS Forms a Complex with PARP1 Distinct from Its Complex with TIPIN and Plays a Role in the DNA Damage Response. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Young LM, Marzio A, Perez-Duran P, Reid DA, Meredith DN, Roberti D, Star A, Rothenberg E, Ueberheide B, Pagano M |
Journal | Cell Rep |
Volume | 13 |
Issue | 3 |
Pagination | 451-459 |
Date Published | 2015 Oct 20 |
ISSN | 2211-1247 |
Keywords | Amino Acid Sequence, Binding Sites, Carrier Proteins, Cell Cycle Proteins, Cell Line, Tumor, DNA Damage, DNA Repair, DNA-Binding Proteins, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, Molecular Sequence Data, Nuclear Proteins, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerases, Protein Binding |
Abstract | PARP1 is the main sensor of single- and double-strand breaks in DNA and, in building chains of poly(ADP-ribose), promotes the recruitment of many downstream signaling and effector proteins involved in the DNA damage response (DDR). We show a robust physical interaction between PARP1 and the replication fork protein TIMELESS, distinct from the known TIMELESS-TIPIN complex, which activates the intra-S phase checkpoint. TIMELESS recruitment to laser-induced sites of DNA damage is dependent on its binding to PARP1, but not PARP1 activity. We also find that the PARP1-TIMELESS complex contains a number of established PARP1 substrates, and TIMELESS mutants unable to bind PARP1 are impaired in their ability to bind PARP1 substrates. Further, PARP1 binding to certain substrates and their recruitment to DNA damage lesions is impaired by TIMELESS knockdown, and TIMELESS silencing significantly impairs DNA double-strand break repair. We hypothesize that TIMELESS cooperates in the PARP1-mediated DDR. |
DOI | 10.1016/j.celrep.2015.09.017 |
Alternate Journal | Cell Rep |
PubMed ID | 26456830 |
PubMed Central ID | PMC4618055 |
Grant List | T32 CA009161 / CA / NCI NIH HHS / United States P30 CA016087 / CA / NCI NIH HHS / United States R01 GM057587 / GM / NIGMS NIH HHS / United States R21 CA187612 / CA / NCI NIH HHS / United States GM110385 / GM / NIGMS NIH HHS / United States R01 GM057691 / GM / NIGMS NIH HHS / United States T32GM088118 / GM / NIGMS NIH HHS / United States GM108119 / GM / NIGMS NIH HHS / United States R37-CA076584 / CA / NCI NIH HHS / United States F30 AG038215 / AG / NIA NIH HHS / United States T32 GM088118 / GM / NIGMS NIH HHS / United States CA187612 / CA / NCI NIH HHS / United States R21 GM110385 / GM / NIGMS NIH HHS / United States GM057691 / GM / NIGMS NIH HHS / United States F30AG038215 / AG / NIA NIH HHS / United States R01 GM108119 / GM / NIGMS NIH HHS / United States R37 CA076584 / CA / NCI NIH HHS / United States R01 CA076584 / CA / NCI NIH HHS / United States 5T32CA009161 / CA / NCI NIH HHS / United States / HHMI_ / Howard Hughes Medical Institute / United States P30CA016087 / CA / NCI NIH HHS / United States |
Related Lab:
Related Faculty:
Antonio Marzio, Ph.D.