The E3 ubiquitin ligase RNF20 regulates chromatin structure by monoubiquitinating histone H2B in transcription. Here, we show that RNF20 is localized to double-stranded DNA breaks (DSBs) independently of H2AX and is required for the DSB-induced H2B ubiquitination. In addition, RNF20 is required for the methylation of H3K4 at DSBs and the recruitment of the chromatin-remodeling factor SNF2h. Depletion of RNF20, depletion of SNF2h, or expression of the H2B mutant lacking the ubiquitination site (K120R) compromises resection of DNA ends and recruitment of RAD51 and BRCA1. Consequently, cells lacking RNF20 or SNF2h and cells expressing H2B K120R exhibit pronounced defects in homologous recombination repair (HRR) and enhanced sensitivity to radiation. Finally, the function of RNF20 in HRR can be partially bypassed by forced chromatin relaxation. Thus, the RNF20-mediated H2B ubiquitination at DSBs plays a critical role in HRR through chromatin remodeling.

The missense mutation causing G71R is the first reported polymorphism for UGT1A1, and the mutation is a risk factor for nonphysiologic neonatal hyperbilirubinemia. The high incidence of hyperbilirubinemia in the Japanese may be attributable to the high frequency of this missense mutation.

Cell proliferation and migration in the external granular layer of the mouse cerebellum were studied with autoradiography after cumulative labeling with H3-thymidine. The germinative cells in the external granular layer were considered as externally dislocated matrix cells. Their generation time, presynthetic time, duration of DNA synthesis, postsynthetic time and mitotic time were determined in one-, three-, seven-and ten-day-old mice. The entire sequence of the ontogeny of the external granular cell-system was separated into three consecutive stages; stage 1 or stage of pure external matrix cell proliferation, stage 2 or stage of neuroblast production, and stage 3 or stage of neuroglia differentiation. Production of neuroblasts in the external granular layer at seven and ten days of life and their migration into the internal granular layer were demonstrated by means of autoradiography. Transit times of the neuroblasts migrating across the external mantle layer and the molecular layer of ten-day-old mice were estimated at 21 and four hours, respectively. More than 50% of the inner granular cells migrated from the external granular layer later than ten days of life and almost 81 to 92% were produced later than seven days of postnatal life. In conclusion, on the basis of the matrix cell concept, the authors tried to uniiy observations of previous and present investigators and presented a scheme of pre-and postnatal histogenesis of the mouse cerebellum.

DNA damage is considered a prime factor in multiple spinocerebellar neurodegenerative diseases; however, the DNA lesions underpinning disease etiology are unknown. Here we identify the endogenous accumulation of pathogenic topoisomerase-1-DNA cleavage complexes (Top1cc) in murine models of ataxia telangiectasia and spinocerebellar ataxia with axonal neuropathy 1. We also show that the defective DNA damage response factors in these two diseases cooperatively modulate Top1cc turnover in a non-epistatic and ATM kinase-independent manner. Furthermore, coincident neural inactivation of ATM and DNA single strand break repair factors including tyrosyl-DNA phosphodiesterase-1 or XRCC1 result in increased Top1cc formation and excessive DNA damage and neurodevelopmental defects. Importantly, direct topoisomerase-1 poisoning to elevate Top1cc levels phenocopies the neuropathology of the mouse models above. Our study identifies a critical endogenous pathogenic lesion associated with neurodegenerative syndromes arising from DNA repair deficiency, indicating the essential role that genome integrity plays in preventing disease in the nervous system.