Replisome stalling and stabilization at CGG repeats, which are responsible for chromosomal fragility

Open Access
Publisher Website
Google Scholar
Abstract
Expanded CGG repeats cause chromosomal fragility and hereditary neurological disorders in humans. These repeats adopt unusual structures that block DNA replication in vitro and in unicellular organisms. Mirkin and co-workers asked whether the same holds true in mammalian cells. They find that CGG repeats stall replication forks in a length-dependent, but orientation-independent, manner and do not seem to trigger an intra–S phase checkpoint response. They suggest that fragile sites arise because the cell cycle continues before replication is complete and the under-replicated areas would convert into constrictions and/or double-stranded breaks. Expanded CGG repeats cause chromosomal fragility and hereditary neurological disorders in humans. Replication forks stall at CGG repeats in a length-dependent manner in primate cells and in yeast. Saccharomyces cerevisiae proteins Tof1 and Mrc1 facilitate replication fork progression through CGG repeats. Remarkably, the fork-stabilizing role of Mrc1 does not involve its checkpoint function. Thus, chromosomal fragility might occur when forks stalled at expanded CGG repeats escape the S-phase checkpoint.