Cited by 63BRCA gene mutations in cancerDNA Repair MechanismsGenetic factors in colorectal cancer

Familial breast cancer screening reveals an alteration in the RAP80 UIM domain that impairs DNA damage response function

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Nikkilä, J, Coleman, K A, Morrissey, D, Pylkäs, K, Erkko, H, Messick, T E, Karppinen, S-M, Amelina, A +2 more·2009·Oncogene

Abstract

Germline mutations in two major susceptibility genes, BRCA1 and BRCA2, account for nearly 20% of familial breast cancers. A majority of the remaining genetic factors involved in heritable breast cancer susceptibility are, however, unknown. Recently, a new BRCA1-interacting protein, receptor associated protein 80 (RAP80), was identified. RAP80 plays an important role in BRCA1-mediated DNA damage responses (DDRs) by recruiting BRCA1 to DNA double-strand breaks (DSBs). A comprehensive screening of DNA from affected index cases of 112 BRCA1/BRCA2 mutation-negative Finnish breast cancer families revealed altogether 10 alterations in RAP80, one of which, c.241-243delGAA, resulted in a single glutamic acid deletion at residue 81 in a highly conserved region of ubiquitin interaction motif 1. The resultant delE81 protein product displayed significantly reduced ubiquitin binding and DSB localization. Expression of the RAP80 delE81 allele impaired both BRCA1 and ABRA1 DSB recruitment, thus compromising BRCA1-mediated DDR signaling. Compared with wild-type RAP80, expression of the delE81 allele was associated with a significant increase in cytogenetically detectable chromosomal aberrations, particularly chromatid breaks. Although evidently quite rare, these results suggest that critical constitutional mutations in RAP80 abrogate DDR function and may be involved in genetic predisposition to cancer.

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  • FANCJ is considered a low-to-moderate penetrance breast cancer susceptibility allele associated with modest two- to threefold increases in breast cancer risk.

    “All together, FANCJ is considered a low-to-moderate penetrance breast cancer susceptibility allele and is associated with modest two- to threefold increases in breast cancer risk [9,54].”

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Authors
Nikkilä, J., Coleman, K. A., Morrissey, D., Pylkäs, K., Erkko, H., Messick, T. E., Karppinen, S.-M., Amelina, A., Winqvist, R., & Greenberg, R. A.
Affiliations
  • Oulu University Hospital (FI)
  • Abramson Cancer Center (US)
Corresponding author
  • Winqvist, R
  • Greenberg, R A
Venue
Oncogene
Published
2009-03-23
Volume
28
Issue
16
Pages
1843-1852
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
OpenAlex
W2081538118
Cited by
63
References
53
Citations by year
2026: 1 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 3 · 2019: 4 · 2018: 3 · 2017: 4 · 2016: 5 · 2015: 3 · 2014: 6 · 2013: 8 · 2012: 9
FWCI
4.26
Type
journal article
Language
en
Open access
Locations
  • Oncogene (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Mary Kay Foundation
  • Finnish Cancer Institute
  • National Institutes of Health
  • National Cancer Institute (K08CA106597)
  • National Institute of General Medical Sciences (T32GM007229)
  • Abramson Family Cancer Research Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Keywords
RAP80, hereditary breast cancer, BRCA1, BRCA2, DNA damage response, DNA double-strand breaks, hereditary cancer predisposition, germline mutations, chromosomal abnormalities, chromatid breaks, ubiquitin binding
MeSH terms
Breast Neoplasms, Carrier Proteins, DNA Damage, DNA-Binding Proteins, Female, Humans, Mutation, Nuclear Proteins, Protein Structure, Tertiary, BRCA1 Protein, Ubiquitin, Genomic Instability, DNA Breaks, Double-Stranded, Histone Chaperones

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