Nijmegen breakage syndrome: The clearance pathway for mutant nibrin protein is allele specific

Salewsky, Bastian; Wessendorf, Petra; Hirsch, Daniel; Krenzlin, Harald; Digweed, Martin

doi:10.1016/j.gene.2013.02.033

Cited by 5 publications

(4 citation statements)

References 35 publications

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“…Remarkably, p70 variation among NBS patients is not determined at the transcription level, but rather by protein stability. Indeed, in vitro inhibition of the proteasome increases cellular levels of p70 [116] . Lastly, the irradiation of cells transfected with p26 caused its interaction with two proteasomal components ( i.e.…”

Section: Resultsmentioning

confidence: 99%

Identification of the Interactors of Human Nibrin (NBN) and of Its 26 kDa and 70 kDa Fragments Arising from the NBN 657del5 Founder Mutation

et al. 2014

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Nibrin (also named NBN or NBS1) is a component of the MRE11/RAD50/NBN complex, which is involved in early steps of DNA double strand breaks sensing and repair. Mutations within the NBN gene are responsible for the Nijmegen breakage syndrome (NBS). The 90% of NBS patients are homozygous for the 657del5 mutation, which determines the synthesis of two truncated proteins of 26 kDa (p26) and 70 kDa (p70). Here, HEK293 cells have been exploited to transiently express either the full-length NBN protein or the p26 or p70 fragments, followed by affinity chromatography enrichment of the eluates. The application of an unsupervised proteomics approach, based upon SDS-PAGE separation and shotgun digestion of protein bands followed by MS/MS protein identification, indicates the occurrence of previously unreported protein interacting partners of the full-length NBN protein and the p26 fragment containing the FHA/BRCT1 domains, especially after cell irradiation. In particular, results obtained shed light on new possible roles of NBN and of the p26 fragment in ROS scavenging, in the DNA damage response, and in protein folding and degradation. In particular, here we show that p26 interacts with PARP1 after irradiation, and this interaction exerts an inhibitory effect on PARP1 activity as measured by NAD+ levels. Furthermore, the p26-PARP1 interaction seems to be responsible for the persistence of ROS, and in turn of DSBs, at 24 h from IR. Since some of the newly identified interactors of the p26 and p70 fragments have not been found to interact with the full-length NBN, these interactions may somehow contribute to the key biological phenomena underpinning NBS.

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Section: Resultsmentioning

confidence: 99%

Identification of the Interactors of Human Nibrin (NBN) and of Its 26 kDa and 70 kDa Fragments Arising from the NBN 657del5 Founder Mutation

et al. 2014

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“…Other breast cancer susceptibility genes have recessive phenotypes associated with biallelic PVs, including Fanconi Anemia for BRCA2 and PALB2, Ataxia Telangiectasia for ATM, and Nijmegen Breakage Syndrome for NBN [13,[20][21][22]. CHEK2 is distinguished by not having a defined recessive phenotype [23].…”

Section: Discussionmentioning

confidence: 99%

“…Despite known and possible cancer associations for CHEK2 PV carriers, phenotypic differences between monoallelic and biallelic carriers are not yet understood. Biallelic carriers of PVs in other, dominant breast cancer susceptibility genes such as BRCA2, ATM, PALB2, and NBN are known to have more severe cancer phenotypes than monoallelic carriers [11][12][13]. Similar patterns for CHEK2 PV carriers have yet to be adequately established.…”

Section: Introductionmentioning

confidence: 99%

High risk of breast cancer in women with biallelic pathogenic variants in CHEK2

Rainville

Hatcher

Rosenthal

et al. 2020

Breast Cancer Res Treat

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Purpose Compared to breast cancer risk genes such as BRCA2, ATM, PALB2, and NBN, no defined phenotype is currently associated with biallelic pathogenic variants (PVs) in CHEK2. This study compared the prevalence of breast and other cancers in women with monoallelic and biallelic CHEK2 PVs. Methods CHEK2 PV carriers were identified through commercial hereditary cancer panel testing (09/2013–07/2019). We compared cancer histories of 6473 monoallelic carriers to 31 biallelic carriers. Breast cancer risks were estimated using multivariate logistic regression and are reported as odds ratios (OR) with 95% confidence intervals (CI). Results Breast cancer frequency was higher among biallelic CHEK2 PV carriers (80.6%, 25/31) than monoallelic carriers (41.2%, 2668/6473; p < 0.0001). Biallelic carriers were more likely to be diagnosed at or before age 50 (61.3%, 19/31) and to have a second breast cancer diagnosis (22.6%, 7/31) compared to monoallelic carriers (23.9%, 1548/6473; p < 0.0001 and 8.1%, 523/6473; p = 0.0107, respectively). Proportionally more biallelic carriers also had any cancer diagnosis and > 1 primary diagnosis. Compared to women with no PVs, biallelic PV carriers had a higher risk of developing ductal invasive breast cancer (OR 8.69, 95% CI 3.69–20.47) and ductal carcinoma in situ (OR 4.98, 95% CI 2.00–12.35) than monoallelic carriers (OR 2.02, 95% CI 1.90–2.15 and OR 1.82, 95% CI 1.66–2.00, respectively). Conclusions These data suggest that biallelic CHEK2 PV carriers have a higher risk for breast cancer, are more likely to be diagnosed younger, and to have multiple primary breast cancers compared to monoallelic carriers. Biallelic carriers also appear to have a higher risk of cancer overall. Therefore, more aggressive management may be appropriate for women with biallelic PVs in CHEK2 compared with current recommendations for monoallelic carriers.

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“…ATM phosphorylates nibrin in response to ionizing radiation. 160 Nibrin and ATM have overlapping functions, leading to clinical and cellular features that are common to both A-T and NBS.…”

Section: Pathogenesismentioning

confidence: 99%

DNA Repair Defects

Porras

2014

Stiehm's Immune Deficiencies

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Nijmegen breakage syndrome: The clearance pathway for mutant nibrin protein is allele specific

Cited by 5 publications

References 35 publications

Identification of the Interactors of Human Nibrin (NBN) and of Its 26 kDa and 70 kDa Fragments Arising from the NBN 657del5 Founder Mutation

Identification of the Interactors of Human Nibrin (NBN) and of Its 26 kDa and 70 kDa Fragments Arising from the NBN 657del5 Founder Mutation

High risk of breast cancer in women with biallelic pathogenic variants in CHEK2

DNA Repair Defects

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