J.S. Hoffmann

  Regulation of DNA replication and genetic instability in cancers

 

 

 

 

 

Our research project at a glance

 

The past decade has seen a dramatic advance in our understanding of how genomic integrity is compromised in cancer and has revealed that replicative stress (RS) in S phase, which leads to chromosomal breakage and unresolved DNA, is a highly relevant mechanism, placing RS studies at the forefront of cancer research.

Our team is exploring:

  • how genetic, environmental, and cell signaling sources can explain RS in several types of cancers,
  • how the transmission of unresolved DNA regions to the next cell generation can be essential for cancer progression and therapeutic resistance.

 

Objectives

 

The team, by exploring these issues, have ultimately opened novel research lines. We have discovered that daughter cells can modify their own replication program to better ensure replication of DNA sequences that experienced problems in the previous cell cycle. This process may explain why a cancer cellular clone could sustain efficient DNA replication and cell proliferation despite a high degree of endogenous replicative stress and unstable genome, a major question that is still unsolved. Our research lines have also revealed a novel crosstalk pathway between replication and repair of damaged DNA, a process that could equip a malignant cellular clone with an escape mechanism in presence of chemotherapeutic treatments which target DNA replication forks and exacerbate replicative stress and, hence, provoke therapeutic resistance.

Our main objectives are:

  • to study the mechanisms used by mother cells to limit the transmission of the replication problems,
  • to monitor the fate of the transmitted damages in G1 daughter cells,
  • to analyze a totally unexplored field, the impact of transmitted DNA damage on the DNA Replication initiation program,
  • to explore the physiological and pathological relevance of the process of DNA damage transmission and its impact on DNA replication of daughter cells,
  • to evaluate how these processes contribute to the therapeutic response of tumors treated with the multiple anticancer agents that impede the progression of the replication forks.

 

Key words

 

  • Replicative stress
  • Genetic instability
  • Therapeutic resistance

 

Selected publications


2017

Lai, X N; Broderick, R; Bergoglio, V; Zimmer, J; Badie, S; Niedzwiedz, W; Hoffmann, J S; Tarsounas, M

MUS81 nuclease activity is essential for replication stress tolerance and chromosome segregation in BRCA2-deficient cells Journal Article

Nature Communications, 8 , 2017, ISSN: 2041-1723.

Links | BibTeX

2016

David, L; Fernandez-Vidal, A; Bertoli, S; Grgurevic, S; Lepage, B; Deshaies, D; Prade, N; Cartel, M; Larrue, C; Sarry, J E; Delabesse, E; Cazaux, C; Didier, C; Recher, C; Manenti, S; Hoffmann, J S

CHK1 as a therapeutic target to bypass chemoresistance in AML Journal Article

Science Signaling, 9 (445), 2016, ISSN: 1945-0877.

Links | BibTeX

Garcia-Exposito, L; Bournique, E; Bergoglio, V; Bose, A; Barroso-Gonzalez, J; Zhang, S F; Roncaioli, J L; Lee, M; Wallace, C T; Watkins, S C; Opresko, P L; Hoffmann, J S; O'Sullivan, R J

Proteomic Profiling Reveals a Specific Role for Translesion DNA Polymerase eta in the Alternative Lengthening of Telomeres Journal Article

Cell Reports, 17 (7), pp. 1858-1871, 2016, ISSN: 2211-1247.

Links | BibTeX

Mansilla, S F; Bertolin, A P; Bergoglio, V; Pillaire, M J; Besteiro, M A G; Luzzani, C; Miriuka, S G; Cazaux, C; Hoffmann, J S; Gottifredi, V

Cyclin Kinase-independent role of p21(cDKN1A) in the promotion of nascent DNA elongation in unstressed cells Journal Article

Elife, 5 , 2016, ISSN: 2050-084x.

Links | BibTeX

2014

Fernandez-Vidal, A; Guitton-Sert, L; Cadoret, J C; Drac, M; Schwob, E; Baldacci, G; Cazaux, C; Hoffmann, J S

A role for DNA polymerase theta in the timing of DNA replication Journal Article

Nature Communications, 5 , 2014, ISSN: 2041-1723.

Links | BibTeX

2013

Bergoglio, V; Boyer, A S; Walsh, E; Naim, V; Legube, G; Lee, M Y W T; Rey, L; Rosselli, F; Cazaux, C; Eckert, K A; Hoffmann, J S

DNA synthesis by Pol eta promotes fragile site stability by preventing under-replicated DNA in mitosis Journal Article

Journal of Cell Biology, 201 (3), pp. 395-408, 2013, ISSN: 0021-9525.

Links | BibTeX

Betous, R; Pillaire, M J; Pierini, L; van der Laan, S; Recolin, B; Ohl-Seguy, E; Guo, C X; Niimi, N; Gruz, P; Nohmi, T; Friedberg, E; Cazaux, C; Maiorano, D; Hoffmann, J S

DNA polymerase kappa-dependent DNA synthesis at stalled replication forks is important for CHK1 activation Journal Article

Embo Journal, 32 (15), pp. 2172-2185, 2013, ISSN: 0261-4189.

Links | BibTeX