Interplay between genomic replication, transcription and chromatin: from stability to plasticity
María Gómez Vicentefranqueira
Centro de Biología Molecular Severo Ochoa (CSIC/UAM)
Copying and decoding the genomic information in a timely and accurate fashion is essential for life. Both tasks (DNA replication and transcription) are remarkably complex in scale and regulation, and the molecular machineries involved in them translocate on the same chromatin template, often in opposite directions and at different rates. This impose cells to employ efficient mechanisms to coordinate both processes which, very likely, in turn influence many key parameters of cellular function, including genome organization, chromatin structure or mutagenesis rates. Recent work from our laboratory showed that appropriate RNA turnover in chromatin is essential to avoid replicative stress and limit replication-transcription conflicts, and unveiled an unexpected role of histone H1 on RNA post-transcriptional modifications. In particular, we found that non-coding RNA retention in chromatin associates with reduced levels of m6A in histone H1-depleted cells, resulting in increased stability of chromatin-bound RNAs and R-loops accumulation, which in turn generates problems with incoming DNA replication forks. Interestingly, accumulation of low-m6A RNAs on chromatin also occurs upon challenging WT cells with different chemotherapeutic drugs that generate DNA damage, like doxorubicin (doxo) or 5-fluorouracil (5-FU), raising the hypothesis that reductions of m6A levels on chromatin-RNAs might constitute a general response to cellular stress to reorganize chromatin architecture.