On November 17, 2023, the Conférence Monod-Diderot will welcome Julian E. Sale (MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge) who will speak on the theme:
Genomic determinants of mutation and epimutation
“The ability of certain DNA sequences to form secondary structures means that DNA itself can pose one of the most potent barriers to its own replication. I will explore how impediments to processive replication can lead to local, heritable loss of epigenetic information. Our recent work that suggests that even short sequences with structure-forming potential that were previously not thought to impede replication actually do cause transient polymerase stalling (Šviković et al., 2019) and that secondary structure is sensed by a core component of the replisome, Timeless (Lerner et al., 2020). I will discuss the relationship between sequence, structure formation and mutagenesis. I will show how the response of a polymerase in a simple primer extension assay can make predictions about the structure that a given sequence forms and that this correlates with the extent to which the sequence is maintained or mutated in the genome during evolution. The data suggest how relatively simple replication parameters may determine the genome wide distribution and stability of short tandem repeats (Murat et al., 2020). I will develop this theme by discussing our recent work on genomic determinants of mutagenesis, focussing on replication origin firing and DNA supercoiling.
I will discuss our recent creation of a high-resolution map of replication origin location and efficiency in human cells with which we have been able to demonstrate that within the set of all origins that have been mapped, a subset of early origins is extremely efficient, likely firing in most cell cycles (Guilbaud et al., 2022). We have shown by isolating this set of highly efficient origins that the act of replication initiation is mutagenic (Murat et al., 2022). I will explore the mechanisms of this mutagenesis and its potential consequences for genome evolution. I will also present very recent unpublished data on mapping DNA supercoiling and the potential impacts of supercoiling on genome function, topology and mutability.”
Julian E. Sale’s lab:
Julian E.Sale’s lab is interested in the mechanisms that alleviate arrested DNA replication and the impact their loss has on mutagenesis and on the maintenance of epigenetic memory through the recycling of histones during replication.
Replication can be arrested by DNA damage or by naturally occurring DNA secondary structures. The lab is particularly interested in translesion synthesis (TLS), which is mediated by specialised DNA polymerases and which is required for replication of both DNA damage and a particular secondary structure called a G quadruplex. Although TLS is potentially mutagenic it plays a critical role in normal cells and understanding its control is central to understanding cell transformation.
The lab study these processes using the powerful combination of vertebrate somatic cell genetics coupled with biochemical, biophysical and advanced optical microscopy techniques to monitor the molecular choreography of proteins and DNA at sites of stalled replication.