Description of the PhD thesis project
DNA replication is an essential fundamental
biology process. Replication program must adapt to changes in chromatin
organization associated with cell differentiation and development, whose
deregulation can challenge genome stability and leads to mutations, cancer and
many other human diseases.
However, despite intensive studies, the
mechanisms that coordinate where and when replication initiates in the human
genome remain poorly known.
Our team focuses on using cutting-edge single
cell and high-throughput genomic approaches to study the spatio-temporal
replication program of the human genome and its impact on genome stability.
Breast Cancer (BC) is the most frequently diagnosed cancer in women, in which
Estrogen (E2) plays a critical role in the carcinogenesis of estrogen-receptor
(ER)-positive BC (75% of all BC cases), while the underlying molecular
mechanisms are still unclear. Transcriptional changes induced by E2 in ER+ BC
cells, promote R-loop formation, strongly correlated with the genome
instability observed in replicating cells. It highly suggests that the observed
genome instability might result from transcription-replication conflicts
We and others have recently shown that, during
replication stress, there is an increased head-on (HO) orientation replication,
causing TRCs and R-loops.
The aim of the current PhD project is to study
the link between transcription, DNA replication, R-loop modification and genome
instability in both cell line model as well as breast cancer patient samples,
in order to understand how E2 induces TRCs, R-loops and DNA damage, and their
role in breast cancer development.
The results from human samples of ER+ breast
cancer patients and PDX models will contribute to identify new predictive
biomarkers in cancer prevention and treatment.
International, interdisciplinary & intersectoral aspects of the project
This is an interdisciplinary project
addressing important fundamental biology question and with high clinical
potential. The proposal will take advantages of merging molecular and cell
biology techniques, high throughput sequencing/imaging approaches and
bioinformatics/biostatistics analyses, providing novel data in understanding
the TRCs and R-loop relationship in the E2-induced genome instability in breast
During the PhD project, the student will
collaborate with the other team members (both experimental and computational
biologists), colleges at Curie hospital, and the world-wide experts in the
corresponding fields, as well as with the industry collaborators (such as
1. Wang W*, Klein K*, Proesmans K*, Yang H*,
Marchal C*, Zhu X*, Borrman T*, Hastie A*, Weng Z*, Bechhoefer J#, CHEN C.L.# (#co-last authors), Gilbert
D.M.# and Rhind N#. (2020) Genome-Wide Mapping of Human DNA Replication by
Optical Replication Mapping Supports a Stochastic Model of Eukaryotic
Replication Timing. bioRxiv. https://doi.org/10.1101/2020.08.24.263459. Mol.
Cell. Under revision.
2. Gnan S., Liu Y., Spagnuolo M., CHEN C.L.
(2020) Impact of transcription-mediated replication stress on genome
instability and human disease. Genome Instability & Disease (GIAD).
1:207-234. Invited review, doi: http://doi.org/10.1007/s42764-020-00021-y.
3. Promonet A.*, Padioleau I.*, Liu Y.*
(*co-first authors), Sanz L., Biernacka A., Schmitz1 A.L., Skrzypczak M.,
Skrzypczak M., Sarrazin A., Mettling C., Rowicka M., Ginalski K., Chedin F., CHEN C.L.# (#co-last authors), Lin
Y.L.# and Pasero P.# (2020) Topoisomerase 1 prevents replication stress at
R-loop-enriched transcription termination sites. Nat. Commun. 11:3940.
(featured as Editors’ Highlights) https://doi.org/10.1038/s41467-020-17858-2.
4. Brison O.*, EL-Hilali S.*, Azar D.,
Koundrioukoff S., Schmidt M, Naehse-Kumpf V., Jaszczyszyn Y., Lachages A.M.,
Dutrillaux B., Thermes C., Debatisse M. and CHEN C.L. (2019) Transcription-Mediated Organization of the
Replication Initiation Program Across Large Genes Sets Common Fragile Sites
Genome-Wide. bioRxiv, doi: https://doi.org/10.1101/714717, Nat. Commun.
10:5693. https://doi.org/10.1038/s41467-019-13674-5 (featured as Editors’
5. Petryk N., Kahli M., d'Aubenton-Carafa Y.,
Jaszczsyzyn Y., Shen Y., Sylvain M., Thermes C., CHEN C.L.# (#co-last authors) and Hyrien O.# (2016) Replication
landscape of the human genome. Nat. Commun. 7:10208 (cited by Faculty of 1000).
Time Cited: 125.