NEIL1 p.Gln282Stop variant is predominantly localized in the cytoplasm and exhibits reduced activity in suppressing mutations

Shinmura, Kazuya; Kato, Hisami; Kawanishi, Yuichi; Goto, Masanori; Hong, Tao; Inoue, Yusuke; Nakamura, Shuichi; Sugimura, Haruhiko

doi:10.1016/j.gene.2015.06.043

Cited by 8 publications

(5 citation statements)

References 39 publications

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“…Therefore, we consider it likely that the reduction in nuclear hRAD52 S346X protein is responsible for the decreased repair of DSBs via SSA. Supporting our hypothesis, it has been shown that the protein encoded by the germline NEIL1 Q282X variant also lacks a C‐terminal NLS, resulting in reduced nuclear localization of the protein (Shinmura et al , 2015). The NEIL1 DNA glycosylase is involved in repair of oxidized bases via the base excision repair pathway, and the Q282X variant displays a diminished ability to suppress mutations (Shinmura et al , 2015).…”

Section: Discussionsupporting

confidence: 77%

“…Supporting our hypothesis, it has been shown that the protein encoded by the germline NEIL1 Q282X variant also lacks a C‐terminal NLS, resulting in reduced nuclear localization of the protein (Shinmura et al , 2015). The NEIL1 DNA glycosylase is involved in repair of oxidized bases via the base excision repair pathway, and the Q282X variant displays a diminished ability to suppress mutations (Shinmura et al , 2015). Since hRAD52 S346X still has all the other known functional domains (Fig.…”

Section: Discussionsupporting

confidence: 77%

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The RAD52 S346X variant reduces risk of developing breast cancer in carriers of pathogenic germline BRCA2 mutations

et al. 2020

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Women who carry pathogenic mutations in BRCA1 and BRCA2 have a lifetime risk of developing breast cancer of up to 80%. However, risk estimates vary in part due to genetic modifiers. We investigated the association of the RAD52 S346X variant as a modifier of the risk of developing breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. The RAD52 S346X allele was associated with a reduced risk of developing breast cancer in BRCA2 carriers [per-allele hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.56-0.86; P = 0.0008] and to a lesser extent in BRCA1 carriers (per-allele HR = 0.78, 95% CI 0.64-0.97, P = 0.02). We examined how this variant affected DNA repair. Using a reporter system that measures repair of DNA double-strand breaks (DSBs) by single-strand annealing (SSA), expression of hRAD52 suppressed the loss of this repair in Rad52 À/À mouse embryonic stem cells. When hRAD52 S346X was expressed in these cells, there was a significantly reduced frequency of SSA. Interestingly, expression of hRAD52 S346X also reduced the stimulation of SSA observed upon depletion of BRCA2, demonstrating the reciprocal roles for RAD52 and BRCA2 in the control of DSB repair by SSA. From an immunofluorescence analysis, we observed little nuclear localization of the mutant protein as compared to the wild-type; it is likely that the reduced nuclear levels of RAD52 S346X explain the diminished DSB repair by SSA. Altogether, we identified a genetic modifier that protects against breast cancer in women who carry pathogenic mutations in BRCA2 (P = 0.0008) and to a lesser extent BRCA1 (P = 0.02). This RAD52 mutation causes a reduction in DSB repair by SSA, suggesting that defects in RAD52-dependent DSB repair are linked to reduced tumor risk in BRCA2-mutation carriers.Abbreviations CI, confidence interval; CIMBA, Consortium of Investigators of Modifiers of BRCA1/2; DSB, DNA double-strand break; GFP, green fluorescent protein; HDR, homology-directed repair; HR, hazard ratio; MAF, minor allele frequency; mESCs, mouse embryonic stem cells;

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Section: Discussionsupporting

confidence: 77%

Section: Discussionsupporting

confidence: 77%

The RAD52 S346X variant reduces risk of developing breast cancer in carriers of pathogenic germline BRCA2 mutations

et al. 2020

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“…The NLS in NEIL1 has not been characterized. A recent study reported that the NEIL1 variant Q282Stop does not translocate to the nucleus, which the authors attributed to the absence of a putative NLS encompassing aa 359-378 in this variant [48]. Our recent study showing that nuclear localization of the truncated N1-311 NEIL1 mutant was comparable to that of the WT enzyme [32], suggests retention of the NLS in the truncated protein, presumably localized in the positive charge patch containing the acetylable Lys residues.…”

Section: Discussionmentioning

confidence: 87%

Acetylation of oxidized base repair-initiating NEIL1 DNA glycosylase required for chromatin-bound repair complex formation in the human genome increases cellular resistance to oxidative stress

et al. 2018

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Posttranslational modifications of DNA repair proteins have been linked to their function. However, it is not clear if posttranslational acetylation affects subcellular localization of these enzymes. Here, we show that the human DNA glycosylase NEIL1, which is involved in repair of both endo- and exogenously generated oxidized bases via the base excision repair (BER) pathway, is acetylated by histone acetyltransferase p300. Acetylation occurs predominantly at Lys residues 296, 297 and 298 located in NEIL1's disordered C-terminal domain. NEIL1 mutant having the substitution of Lys 296-298 with neutral Ala loses nuclear localization, whereas Lys > Arg substitution (in 3KR mutant) at the same sites does not affect NEIL1's nuclear localization or chromatin binding, presumably due to retention of the positive charge. Although non-acetylated NEIL1 can bind to chromatin, acetylated NEIL1 is exclusively chromatin-bound. NEIL1 acetylation while dispensable for its glycosylase activity enhances it due to increased product release. The acetylation-defective 3KR mutant forms less stable complexes with various chromatin proteins, including histone chaperones and BER/single-strand break repair partners, than the wild-type (WT) NEIL1. We also showed that the repair complex with WT NEIL1 has significantly higher BER activity than the 3KR mutant complex. This is consistent with reduced resistance of non-acetylable mutant NEIL1 expressing cells to oxidative stress relative to cells expressing the acetylable WT enzyme. We thus conclude that the major role of acetylable Lys residues in NEIL1 is to stabilize the formation of chromatin-bound repair complexes which protect cells from oxidative stress.

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“…So far, several forms of germline nonsynonymous NEIL1 or NEIL2 mutations have been experimentally demonstrated to actually have reduced or absent repair activity [ 10 , 11 , 29 , 30 ]. Human cells containing such NEIL1 or NEIL2 mutations are considered to have a reduced capacity to repair mutagenic bases; thus, similar to cancers with a reduced NEIL1 or NEIL2 expression levels, a higher incidence of mutation is likely to occur in the cells, leading to cancer susceptibility.…”

Section: Discussionmentioning

confidence: 99%

“…Because of these DNA glycosylase activities, NEIL1, NEIL2, and NEIL3 also have the ability to regulate the mutation frequency in cells. Deficiencies of NEIL1 or NEIL2 in mammalian cells reportedly lead to an elevated mutation frequency [ 9 – 11 ], and the overproduction of mouse NEIL3 in an E. coli fpg nei mutY strain reduced the spontaneous mutation frequency [ 12 ]. These findings indicate that NEIL1, NEIL2, and NEIL3 have the ability to suppress mutations in cells.…”

Section: Introductionmentioning

confidence: 99%

Abnormal Expressions of DNA Glycosylase Genes NEIL1, NEIL2, and NEIL3 Are Associated with Somatic Mutation Loads in Human Cancer

Shinmura

Kato

Kawanishi

et al. 2016

Oxidative Medicine and Cellular Longevity

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The effects of abnormalities in the DNA glycosylases NEIL1, NEIL2, and NEIL3 on human cancer have not been fully elucidated. In this paper, we found that the median somatic total mutation loads and the median somatic single nucleotide mutation loads exhibited significant inverse correlations with the median NEIL1 and NEIL2 expression levels and a significant positive correlation with the median NEIL3 expression level using data for 13 cancer types from the Cancer Genome Atlas (TCGA) database. A subset of the cancer types exhibited reduced NEIL1 and NEIL2 expressions and elevated NEIL3 expression, and such abnormal expressions of NEIL1, NEIL2, and NEIL3 were also significantly associated with the mutation loads in cancer. As a mechanism underlying the reduced expression of NEIL1 in cancer, the epigenetic silencing of NEIL1 through promoter hypermethylation was found. Finally, we investigated the reason why an elevated NEIL3 expression level was associated with an increased number of somatic mutations in cancer and found that NEIL3 expression was positively correlated with the expression of APOBEC3B, a potent inducer of mutations, in diverse cancers. These results suggested that the abnormal expressions of NEIL1, NEIL2, and NEIL3 are involved in cancer through their association with the somatic mutation load.

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NEIL1 p.Gln282Stop variant is predominantly localized in the cytoplasm and exhibits reduced activity in suppressing mutations

Cited by 8 publications

References 39 publications

The RAD52 S346X variant reduces risk of developing breast cancer in carriers of pathogenic germline BRCA2 mutations

The RAD52 S346X variant reduces risk of developing breast cancer in carriers of pathogenic germline BRCA2 mutations

Acetylation of oxidized base repair-initiating NEIL1 DNA glycosylase required for chromatin-bound repair complex formation in the human genome increases cellular resistance to oxidative stress

Abnormal Expressions of DNA Glycosylase Genes NEIL1, NEIL2, and NEIL3 Are Associated with Somatic Mutation Loads in Human Cancer

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