A novel Ku70 function in colorectal homeostasis separate from nonhomologous end joining

Abstract

Ku70, a known nonhomologous end-joining (NHEJ) factor, also functions in tumor suppression, although this molecular mechanism remains uncharacterized. Previously, we showed that mice deficient for DNA ligase IV (Lig4), another key NHEJ factor, succumbed to aggressive lymphoma in the absence of tumor suppressor p53. However, the tumor phenotype is abrogated by the introduction of a hypomorphic mutant p53R172P, which impaired p53-mediated apoptosis but not cell-cycle arrest. However, Lig4−/−p53R172P mice succumbed to severe diabetes. To further elucidate the role of NHEJ and p53-mediated apoptosis in vivo, we bred Ku70−/−p53R172P mice. Unexpectedly, these mice were free of diabetes, although 80% of the mutant mice had abnormally enlarged colons with pronounced inflammation. Remarkably, most of these mutant mice progressed to dysplasia, adenoma and adenocarcinoma; this is in contrast to the Lig4−/−p53R172P phenotype, strongly suggesting an NHEJ-independent function of Ku70. Significantly, our analyses of Ku70−/−p53R172P colonic epithelial cells show nuclear stabilization of β-catenin accompanied by higher expression of cyclin D1 and c-Myc in affected colon sections than in control samples. This is not due to the p53 mutation, as Ku70−/− mice share this phenotype. Our results not only unravel a novel function of Ku70 essential for colon homeostasis, but also establish an excellent in vivo model in which to study how chronic inflammation and abnormal cellular proliferation underlie tumorigenesis and tumor progression in the colon.

Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes

“…The Xrcc4 protein is a critical binding partner of DNA ligase IV (Lig4). Lig4 knockout mice develop spontaneous diabetes due to poor double-stranded DNA break (DSB) repair in beta cells, leading to senescence 21,22 . We found two polymorphisms in the NOD Xrcc4 allele (Fig.…”

Fusobacterium nucleatumCaused DNA Damage and Promoted Cell Proliferation by theKu70/p53Pathway in Oral Cancer Cells

“…Thus, combined with the results above, we concluded that the possible promoting role of F. nucleatum in OSCC relied on the Ku70/p53 pathway after causing DNA damage. Ku70 is known as the key component of classic NHEJ that plays a critical role in detecting DSBs (Puebla-Osorio et al, 2014). Thus, in the present study, we focused the specific role of Ku70 in DNA damage caused by F. nucleatum infection.…”

Association Between the XRCC6 Polymorphisms and Cancer Risks

“…XRCC6 gene was involved in multiple cellular pathways, including NHEJ pathway of DSB repair. 40 , 41 During DNA repair procedure, Ku70 acted as a scaffold to recruit the other NHEJ factors to the damage site after its bound to DNA ends. 4 However, inaccurate repair could lead to cellular aberrant function, apoptosis, and chromosomal rearrangements, which promote carcinogenesis finally.…”