Law, P. P. | Search bioRxiv

bioRxiv2019

TRF1 prevents permissive DNA damage response, recombination and Break Induced Replication at telomeres

Telomeres are a significant challenge to DNA replication and are prone to replication stress and telomere fragility. The shelterin component TRF1 facilitates telomere replication but the molecular mechanism remains uncertain. By interrogating the proteomic composition of telomeres, we show that telomeres lacking TRF1 undergo protein composition reorganisation associated with a DNA damage response and chromatin remodelers. Surprisingly, TRF1 suppresses the accumulation of promyelocytic leukemia (PML) protein, BRCA1 and the SMC5/6 complex at telomeres, which is associated with increased Homologous Recombination (HR) and TERRA transcription. We uncovered a previously unappreciated role for TRF1 in the suppression of telomere recombination, dependent on SMC5 and also POLD3 dependent Break Induced Replication at telomeres. We propose that TRF1 facilitates S-phase telomeric DNA synthesis to prevent illegitimate mitotic DNA recombination and chromatin rearrangement.

cell biology↗

bioRxiv2019

Sex differences in gene expression and proliferation are dependent on the epigenetic modifier HP1γ

Sex differences in growth rate in very early embryos have been recognized in a variety of mammals and attributed to sex-chromosome complement effects as they occur before overt sexual differentiation. We previously found that sex-chromosome complement, rather than sex hormones regulates heterochromatin-mediated silencing of a transgene and autosomal gene expression in mice. Here, sex dimorphism in proliferation was investigated. We confirm that male embryonic fibroblasts proliferate faster than female fibroblasts and show that this proliferation advantage is completely dependent upon heterochromatin protein 1 gamma (HP1{gamma}). To determine whether this sex-regulatory effect of HP1{gamma} was a more general phenomenon, we performed RNA sequencing on MEFs derived from males and females, with or without HP1{gamma}. Strikingly, HP1{gamma} was found to be crucial for regulating nearly all sexually dimorphic autosomal gene expression because deletion of the HP1{gamma} gene in males abolished sex differences in autosomal gene expression. The identification of a key epigenetic modifier as central in defining gene expression differences between males and females has important implications for understanding physiological sex differences and sex bias in disease.

developmental biology↗