PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways

By Minli Wang, Weizhong Wu, Wenqi Wu, Bustanur Rosidi, Lihua Zhang, Huichen Wang, G. Iliakis. Nucleic Acids Research, 2006

865 citations recorded by the source corpus.

Poly(ADP-ribose)polymerase 1 (PARP-1) recognizes DNA strand interruptions in vivo and triggers its own modification as well as that of other proteins by the sequential addition of ADP-ribose to form polymers. This modification causes a release of PARP-1 from DNA ends and initiates a variety of responses including DNA repair. While PARP-1 has been firmly implicated in base excision and single strand break repair, its role in the repair of DNA double strand breaks (DSBs) remains unclear. Here, we show that PARP-1, probably together with DNA ligase III, operates in an alternative pathway of non-homologous end joining (NHEJ) that functions as backup to the classical pathway of NHEJ that utilizes DNA-PKcs, Ku, DNA ligase IV, XRCC4, XLF/Cernunnos and Artemis. PARP-1 binds to DNA ends in direct competition with Ku. However, in irradiated cells the higher affinity of Ku for DSBs and an excessive number of other forms of competing DNA lesions limit its contribution to DSB repair. When essential components of the classical pathway of NHEJ are absent, PARP-1 is recruited for DSB repair, particularly in the absence of Ku and non-DSB lesions. This form of DSB repair is sensitive to PARP-1 inhibitors. The results define the function of PARP-1 in DSB repair and characterize a candidate pathway responsible for joining errors causing genomic instability and cancer.

Subfields: Electrical and Electronic Engineering, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/704fcfaa0ec8ec565e21f9b0e4c47d6f24d78db2

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Citations in the corpus

Alternative-NHEJ Is a Mechanistically Distinct Pathway of Mammalian Chromosome Break Repair (2008, background): “Though, PARP has been shown to play a role in plasmid-based NHEJ assays [11], such that it would be important to ensure that altNHEJ is targeted separately from PARP function.”
The histone methyltransferase SMYD2 methylates PARP1 and promotes poly(ADP-ribosyl)ation activity in cancer cells. (2014, background): “PARP1 has been shown to play multiple critical roles in the repair of DNA single-strand breaks (SSBs) and double strand breaks (DSBs) [4-9].”
MMEJ repair of double-strand breaks (director’s cut): deleted sequences and alternative endings (2008, background): “PARP-1 Human and rodent cell lines Synapsis of ends BER [52, 54 ] Histone H1 Human cell lines Unclear, stimulated or inhibited MMEJ in”
Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. (2011, background): “2008), and Ku also competes with PARP1 for DNA end binding in mammalian cells (Wang et al. 2006).”
Repair Pathway Choices and Consequences at the Double-Strand Break (2015, neutral): “Molecular characterization of this alt-EJ activity in cells lacking C-NHEJ revealed that the XRCC1/DNA ligase III complex and the PARP1 polyribosylating enzyme were involved [10].”
PARP-1 cleavage fragments: signatures of cell-death proteases in neurodegeneration (2010, background): “Initially identified as an enzyme that performs central roles in the repair of damaged DNA, PARP-1 participates in initiating base excision repair (BER) (PARP-1-/- cells have impaired BER activity) [1,2], nucleotide excision repair, single strand base repair mediated by DNA ligase III, XRCC1, poly n”
Homologous recombination deficiency: Exploiting the fundamental vulnerability of ovarian cancer (2015, background): “Molecular characterization of alt-EJ revealed that the XRCC1/ DNA ligase III complex and PARP1 were involved (84, 117, 118).”
Chapter 1. General introduction (2015, neutral): “in the B-NHEJ pathway in mammals (83;85;87), the orthologs of Parp proteins have been”
PARP inhibition: PARP1 and beyond (2010, background): “Additional in vitro studies in rodent and human cells have implicated PARP1 in non-homologous end joining (NHEJ”
The DNA Damage Response: Making it safe to play with knives (2010, background): “As noted above, PARP1/2 also senses DSBs. PARP acts to promote alt-NHEJ, which functions as backup to the classical pathway of NHEJ described above (Figure 2C) (Wang et al., 2006).”