Epigenetic control during embryogenesis

Division Of Basic Sciences - Nci

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Abstract

A hallmark of the ICF4 syndrome is genomic instability with chromosomal aberrations, but the reasons remained unknown. Using knockout mice and knowdwon cell lines, the Epigenetics groups demonstrated that LSH plays an important role in the protection of stalled replication forks. The protection of nascent DNA at stalled forks is mediated by macroH2A, whose knockdown mimics LSH depletion and whose overexpression rescues nascent DNA degradation. The perturbation of chromatin is associated with abnormal histone modification marks that are critical for the recruitment of the DNA repair factors 53BP1 and BRCA1. The balance of 53BP1 and BRCA1 in turn influences RAD51 loading and prevents MRE11 and EXO1 nuclease mediated degradation of nascent DNA. Altogether, their results illuminate the mechanism underlying a human syndrome and reveal a critical role of LSH mediated macroH2A deposition in genome integrity.