4.8 Article

The Kub5-Hera/RPRD1B interactome: a novel role in preserving genetic stability by regulating DNA mismatch repair

期刊

NUCLEIC ACIDS RESEARCH
卷 44, 期 4, 页码 1718-1731

出版社

OXFORD UNIV PRESS
DOI: 10.1093/nar/gkv1492

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资金

  1. National Institutes of Health/National Cancer Institute (NCI/NIH) [R01 CA139217]
  2. NCI/NIH [5P30CA142543]
  3. NCI/NIH [UT Southwestern CCSG grant] [5P30CA142543]
  4. Cancer Biology Training Grant [T32CA124334- 06]
  5. Simmons Comprehensive Cancer Center
  6. Cancer Prevention and Research Institute of Texas [CPRIT] [RP1206130]
  7. [R01 CA139217-05S1]

向作者/读者索取更多资源

Ku70-binding protein 5 (Kub5)-Hera (K-H)/RPRD1B maintains genetic integrity by concomitantly minimizing persistent R-loops and promoting repair of DNA double strand breaks (DSBs). We used tandem affinity purification-mass spectrometry, coimmunoprecipitation and gel-filtration chromatography to define higher-order protein complexes containing K-H scaffolding protein to gain insight into its cellular functions. We confirmed known protein partners (Ku70, RNA Pol II, p15RS) and discovered several novel associated proteins that function in RNA metabolism (Topoisomerase 1 and RNA helicases), DNA repair/replication processes (PARP1, MSH2, Ku, DNA-PKcs, MCM proteins, PCNA and DNA Pol delta) and in protein metabolic processes, including translation. Notably, this approach directed us to investigate an unpredicted involvement of K-H in DNA mismatch repair (MMR) where K-H depletion led to concomitant MMR deficiency and compromised global microsatellite stability. Mechanistically, MMR deficiency in K-H-depleted cells was a consequence of reduced stability of the core MMR proteins (MLH1 and PMS2) caused by elevated basal caspase-dependent proteolysis. Pan-caspase inhibitor treatment restored MMR protein loss. These findings represent a novel mechanism to acquire MMR deficiency/microsatellite alterations. A significant proportion of colon, endometrial and ovarian cancers exhibit k-h expression/copy number loss and may have severe mutator phenotypes with enhanced malignancies that are currently overlooked based on sporadic MSI+ screening.

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