TIMELESS Forms a Complex with PARP1 Distinct from Its Complex with TIPIN and Plays a Role in the DNA Damage Response.

TitleTIMELESS Forms a Complex with PARP1 Distinct from Its Complex with TIPIN and Plays a Role in the DNA Damage Response.
Publication TypeJournal Article
Year of Publication2015
AuthorsYoung LM, Marzio A, Perez-Duran P, Reid DA, Meredith DN, Roberti D, Star A, Rothenberg E, Ueberheide B, Pagano M
JournalCell Rep
Volume13
Issue3
Pagination451-459
Date Published2015 Oct 20
ISSN2211-1247
KeywordsAmino 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.

DOI10.1016/j.celrep.2015.09.017
Alternate JournalCell Rep
PubMed ID26456830
PubMed Central IDPMC4618055
Grant ListT32 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 Faculty: 
Antonio Marzio, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
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