SSRP1 Cooperates with PARP and XRCC1 to Facilitate Single-Strand DNA Break Repair by Chromatin Priming

Gao, Ying; Li, Changling; Wei, Leizhen; Teng, Yaqun; Nakajima, Satoshi; Chen, Xiukai; Xu, Jianquan; Leger, Brittany; Ma, Hongqiang; Spagnol, Stephen T.; Wan, Yong; Dahl, Kris Noel; Liu, Yang; Levine, Arthur S.; Lan, Li

doi:10.1158/0008-5472.can-16-3128

Cited by 37 publications

(37 citation statements)

References 54 publications

(67 reference statements)

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“…The data presented here indicate that the RIR motif is functionally important for DNA strand break repair rates and cell survival following oxidative stress. However, it is currently unclear to what extent the interaction with PNKP accounts for this importance, because this motif also interacts with Rev1 ( 35 ) and with SSRP1 ( 41 ), a component of the FACT chromatin remodeling complex. Further work is required to compare directly the relative affinities of the XRCC1 RIR motif for the three binding partners, but the data available to date suggest that the affinity of XRCC1 for Rev1 in vitro is ∼150-fold lower than its affinity for PNKP ( K d of 5 μ m and 30 n m , respectively).…”

Section: Discussionmentioning

confidence: 99%

The Rev1 interacting region (RIR) motif in the scaffold protein XRCC1 mediates a low-affinity interaction with polynucleotide kinase/phosphatase (PNKP) during DNA single-strand break repair

Breslin

Mani²,

Fanta³

et al. 2017

Journal of Biological Chemistry

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The scaffold protein X-ray repair cross-complementing 1 (XRCC1) interacts with multiple enzymes involved in DNA base excision repair and single-strand break repair (SSBR) and is important for genetic integrity and normal neurological function. One of the most important interactions of XRCC1 is that with polynucleotide kinase/phosphatase (PNKP), a dual-function DNA kinase/phosphatase that processes damaged DNA termini and that, if mutated, results in ataxia with oculomotor apraxia 4 (AOA4) and microcephaly with early-onset seizures and developmental delay (MCSZ). XRCC1 and PNKP interact via a high-affinity phosphorylation-dependent interaction site in XRCC1 and a forkhead-associated domain in PNKP. Here, we identified using biochemical and biophysical approaches a second PNKP interaction site in XRCC1 that binds PNKP with lower affinity and independently of XRCC1 phosphorylation. However, this interaction nevertheless stimulated PNKP activity and promoted SSBR and cell survival. The low-affinity interaction site required the highly conserved Rev1-interacting region (RIR) motif in XRCC1 and included three critical and evolutionarily invariant phenylalanine residues. We propose a bipartite interaction model in which the previously identified high-affinity interaction acts as a molecular tether, holding XRCC1 and PNKP together and thereby promoting the low-affinity interaction identified here, which then stimulates PNKP directly.

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Section: Discussionmentioning

confidence: 99%

The Rev1 interacting region (RIR) motif in the scaffold protein XRCC1 mediates a low-affinity interaction with polynucleotide kinase/phosphatase (PNKP) during DNA single-strand break repair

Breslin

Mani²,

Fanta³

et al. 2017

Journal of Biological Chemistry

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“…DC (aa 1-904) and DN (aa 288-940) PNUTS were obtained by PCR amplification. GFP-PARP1 was characterized as in a previous study (27). PARP1-BRCT (aa 345-540) was obtained by PCR amplification and inserted into the pEGFP-C1 vector for expression.…”

Section: Protein Expression and Pull-downmentioning

confidence: 99%

Phosphatase 1 Nuclear Targeting Subunit Mediates Recruitment and Function of Poly (ADP-Ribose) Polymerase 1 in DNA Repair

et al. 2019

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PARP, particularly PARP1, plays an essential role in the detection and repair of DNA single-strand breaks and double-strand breaks. PARP1 accumulates at DNA damage sites within seconds after DNA damage to catalyze the massive induction of substrate protein poly ADP-ribosylation (PARylation). However, the molecular mechanisms underlying the recruitment and activation of PARP1 in DNA repair are not fully understood. Here we show that phosphatase 1 nuclear targeting subunit 1 (PNUTS) is a robust binding partner of PARP1. Inhibition of PNUTS led to strong accumulation of endogenous DNA damage and sensitized the cellular response to a wide range of DNA-damaging agents, implicating PNUTS as an essential and multifaceted regulator of DNA repair. Recruitment of PNUTS to laser-induced DNA damage was similar to that of PARP1, and depletion or inhibition of PARP1 abrogated recruitment of PNUTS to sites of DNA damage. Conversely, PNUTS was required for efficient induction of substrate PARylation after DNA damage. PNUTS bound the BRCA1 C-terminal (BRCT) domain of PARP1 and was required for the recruitment of PARP1 to sites of DNA damage. Finally, depletion of PNUTS rendered cancer cells hypersensitive to PARP inhibition. Taken together, our study characterizes PNUTS as an essential partner of PARP1 in DNA repair and a potential drug target in cancer therapy. Significance: These findings reveal PNUTS as an essential functional partner of PARP1 in DNA repair and suggest its inhibition as a potential therapeutic strategy in conjunction with DNA-damaging agents or PARP inhibitors. See related commentary by Murai and Pommier, p. 2460

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“…Protein factors of unknown nature that are not involved in chromatin structure remodeling form complex with DNA glycosylase NTH1 and stimulate its activity in BER initiation [85]. The SSRP1 protein entailed in chromatin disassembly as a histone H2A/H2B chaperone interacts with both PAR-PARP1 and XRCC1 and facilitates repair of SSBs [86]. In general, the mechanisms of BER functioning within chromatin are largely unexplored (for example, see [87]), remaining possibility to discover new noncanonical factors of BER.…”

Section: Interactions Of Ber Proteins With Noncanonical Factors Contrmentioning

confidence: 99%

Coordination of DNA Base Excision Repair by Protein-Protein Interactions

Moor¹,

Lavrik²

2019

DNA Repair- An Update

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The system of base excision repair (BER) evolved to correct the most abundant DNA damages in mammalian cells is the most essential for maintaining the genome integrity. The multistep BER process involves several enzymes and protein factors functioning in a coordinated fashion that ensures the repair efficiency. The coordination is facilitated by the formation of protein complexes stabilized via either direct or indirect DNA-mediated interactions. This review focuses on direct interactions of proteins participating in BER with each other and with noncanonical factors found recently to modulate the efficiency of BER. All the known partners of main BER participants, the sites responsible for their interaction, and the characteristics of protein-protein affinity are summarized. Well-documented evidences of how DNA intermediates and posttranslational modifications of proteins modulate protein-protein interactions are presented. The available data allow to suggest that the multiprotein complexes are assembled with the involvement of a scaffold protein XRCC1 and poly(ADP-ribose) polymerase 1, a key regulator of the BER process, irrespective of the DNA damage; the composition and the structure of the complexes are dynamically changed depending on the DNA damage, its chromatin environment, and the step of BER process.

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SSRP1 Cooperates with PARP and XRCC1 to Facilitate Single-Strand DNA Break Repair by Chromatin Priming

Cited by 37 publications

References 54 publications

The Rev1 interacting region (RIR) motif in the scaffold protein XRCC1 mediates a low-affinity interaction with polynucleotide kinase/phosphatase (PNKP) during DNA single-strand break repair

The Rev1 interacting region (RIR) motif in the scaffold protein XRCC1 mediates a low-affinity interaction with polynucleotide kinase/phosphatase (PNKP) during DNA single-strand break repair

Phosphatase 1 Nuclear Targeting Subunit Mediates Recruitment and Function of Poly (ADP-Ribose) Polymerase 1 in DNA Repair

Coordination of DNA Base Excision Repair by Protein-Protein Interactions

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