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

Overview

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.

publication date

  • October 8, 2015

Research

keywords

  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA Damage
  • DNA Repair
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Poly(ADP-ribose) Polymerases

Identity

PubMed Central ID

  • PMC4618055

Scopus Document Identifier

  • 84944684622

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2015.07.031

PubMed ID

  • 26456830

Additional Document Info

volume

  • 13

issue

  • 3