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m links, replaced: journal = Neurobiology of Disease → journal = Neurobiology of Disease (48), ]] ]] → ]] (2), ]] → ]] (46), Immunology → Immunology |
m links, replaced: journal = Neurobiology of Disease → journal = Neurobiology of Disease ]] (48), ]] ]] → ]] (47), DNA Repair → DNA Repair |
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=== Role in DNA damage repair ===
PARP1 acts as a first responder that detects [[DNA damage (naturally occurring)|DNA damage]] and then facilitates choice of [[DNA repair|repair]] pathway.<ref name="Pascal2018">{{cite journal | vauthors = Pascal JM | title = The comings and goings of PARP-1 in response to DNA damage | journal = [[DNA Repair (journal)|DNA Repair]] | volume = 71 | issue = | pages = 177–182 | date = November 2018 | pmid = 30177435 | pmc = 6637744 | doi = 10.1016/j.dnarep.2018.08.022 }}</ref> PARP1 contributes to repair efficiency by [[ADP-ribosylation]] of [[histone]]s leading to decompaction of [[chromatin]] structure, and by interacting with and modifying multiple [[DNA repair]] factors.<ref name="pmid33028824" /> PARP1 is implicated in the regulation of several DNA repair processes including the pathways of [[nucleotide excision repair]], [[non-homologous end joining]], [[microhomology-mediated end joining]], [[homologous recombination]]al repair, and [[DNA mismatch repair]].<ref name=Pascal2018/>
PARP1 has a role in repair of single-stranded DNA (ssDNA) breaks. Knocking down intracellular PARP1 levels with [[siRNA]] or inhibiting PARP1 activity with small molecules reduces repair of ssDNA breaks. In the absence of PARP1, when these breaks are encountered during [[DNA replication]], the [[replication fork]] stalls, and double-strand DNA (dsDNA) breaks accumulate. These dsDNA breaks are repaired via [[homologous recombination]] (HR) repair, a potentially error-free repair mechanism. For this reason, cells lacking PARP1 show a hyper-recombinagenic phenotype (e.g., an increased frequency of HR),<ref name="pmid18603595">{{cite journal | vauthors = Godon C, Cordelières FP, Biard D, Giocanti N, Mégnin-Chanet F, Hall J, Favaudon V | title = PARP inhibition versus PARP-1 silencing: different outcomes in terms of single-strand break repair and radiation susceptibility | journal = [[Nucleic Acids Research]] | volume = 36 | issue = 13 | pages = 4454–64 | date = August 2008 | pmid = 18603595 | pmc = 2490739 | doi = 10.1093/nar/gkn403 }}</ref><ref name="pmid12930944">{{cite journal | vauthors = Schultz N, Lopez E, Saleh-Gohari N, Helleday T | title = Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination | journal = [[Nucleic Acids Research]] | volume = 31 | issue = 17 | pages = 4959–64 | date = September 2003 | pmid = 12930944 | pmc = 212803 | doi = 10.1093/nar/gkg703 }}</ref><ref name="pmid1945881">{{cite journal | vauthors = Waldman AS, Waldman BC | title = Stimulation of intrachromosomal homologous recombination in mammalian cells by an inhibitor of poly(ADP-ribosylation) | journal = [[Nucleic Acids Research]] | volume = 19 | issue = 21 | pages = 5943–7 | date = November 1991 | pmid = 1945881 | pmc = 329051 | doi = 10.1093/nar/19.21.5943 }}</ref> which has also been observed [[in vivo]] in mice using the [[pun assay]].<ref name="pmid20660013">{{cite journal | vauthors = Claybon A, Karia B, Bruce C, Bishop AJ | title = PARP1 suppresses homologous recombination events in mice in vivo | journal = [[Nucleic Acids Research]] | volume = 38 | issue = 21 | pages = 7538–45 | date = November 2010 | pmid = 20660013 | pmc = 2995050 | doi = 10.1093/nar/gkq624 }}</ref> Thus, if the HR pathway is functioning, PARP1 [[null mutant]]s (cells without functioning PARP1) do not show an unhealthy phenotype, and in fact, PARP1 [[knockout mice]] show no negative phenotype and no increased incidence of tumor formation.<ref name="pmid7698643">{{cite journal | vauthors = Wang ZQ, Auer B, Stingl L, Berghammer H, Haidacher D, Schweiger M, Wagner EF | title = Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease | journal = [[Genes & Development]] | volume = 9 | issue = 5 | pages = 509–20 | date = March 1995 | pmid = 7698643 | doi = 10.1101/gad.9.5.509 | doi-access = free }}</ref>
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