Alternative DNA repair in cancer

Raphael Ceccaldi

Raphaël Ceccaldi Team Leader Tel:

Our goal is to understand DNA repair mechanisms that are essential for the survival of cancer cells. Unraveling the function and structure of these mechanisms will facilitate the identification of new targets for the tailored treatment of cancer.

DNA double-strand breaks (DSBs) are cytotoxic lesions that threaten genomic integrity. Failure to repair a DSB can have harmful deleterious consequences, including genomic instability and cell death. Indeed, misrepair of DSBs can lead to inappropriate chromosomic events such as translocations, which commonly underlie oncogenic transformation.

Ceccaldi1
Figure 1. Main focus of our laboratory: the study of double-strand break (DSB) repair mechanisms. (A) Classical (green box) and alternative (blue box) DSB repair pathways. (B) Competition between classical and alternative DSB repair pathways at damaged replication forks. For more details, see Ceccaldi et al., Trends in Cellular Biology, 2015; Nature Reviews Molecular Cell Biology, 2016.

Typically, cells employ two classical mechanisms to repair DSBs: homologous recombination (HR) and nonhomologous end-joining (NHEJ) (Figure 1A, green box). In addition, alternative error-prone DSB repair mechanisms, namely alternative end-joining (alt-EJ) and single strand annealing (SSA), have been recently shown to operate in many different conditions and to contribute to genome rearrangements and oncogenic transformation (Figure 1A, blue box). In human cells, these mechanisms form a complex network composed of four distinct pathways, which can interplay, compete, or even compensate one for the other. For instance, classical and alternative pathways interplay and compete for the repair of DSBs occurring during replication (i.e. damaged replication forks) (Figure 1B).

Our laboratory is particularly interested in studying alternative DNA repair mechanisms, such as the alternative end joining (alt-EJ) pathway, that take place in cancer cells to compensate for the loss of homologous recombination (HR) activity (Figure 2A).

The clinical relevance of our studies relies on the fact that half of ovarian serous carcinomas and basal-like breast cancers entail a defect in HR, which prompts them to rely on alt-EJ for survival (Figure 2B). As a consequence, targeting alt-EJ players emerged as a new promising strategy for the treatment of HR-deficient tumors.

Figure 2. Translational application of our research: finding new drug target for the treatment of HR-deficient cancers. (A) HR-deficient tumors (i.e. mutations of BRCA1 or BRCA2 genes) hyperactivate the alt-EJ pathway and cells become hyperdependent on alt-EJ for survival. As a consequence, loss of both HR and alt-EJ pathways induces cell death, defining a synthetic lethal interaction. (B) Sketch showing our research strategy and objectives. Breast and ovarian cancers frequently harbour genetic alterations in HR genes, which turn into an hyperactivation of the alt-EJ pathway. We aim to fully characterize alt-EJ using a combination of cutting-edge proteomics, molecular and cellular biology approaches. Our main goals are to uncover new DNA repair factors, new crosstalks between repair mechanisms and finally new target for the tailored treatment of HR-deficient tumors. For more details, see Ceccaldi et al. Nature, 2015; Konstantinopoulos et al., Cancer Discovery 2016; Kais et al. Cell Reports 2016.
Figure 2. Translational application of our research: finding new drug target for the treatment of HR-deficient cancers. (A) HR-deficient tumors (i.e. mutations of BRCA1 or BRCA2 genes) hyperactivate the alt-EJ pathway and cells become hyperdependent on alt-EJ for survival. As a consequence, loss of both HR and alt-EJ pathways induces cell death, defining a synthetic lethal interaction. (B) Sketch showing our research strategy and objectives. Breast and ovarian cancers frequently harbour genetic alterations in HR genes, which turn into an hyperactivation of the alt-EJ pathway. We aim to fully characterize alt-EJ using a combination of cutting-edge proteomics, molecular and cellular biology approaches. Our main goals are to uncover new DNA repair factors, new crosstalks between repair mechanisms and finally new target for the tailored treatment of HR-deficient tumors. For more details, see Ceccaldi et al. Nature, 2015; Konstantinopoulos et al., Cancer Discovery 2016; Kais et al. Cell Reports 2016.

While alt-EJ has been studied in lower eukaryotes, little is known about its composition, regulation and mode of action in humans. Our team is using a combination of cutting-edge proteomics, molecular and cellular biology strategies to uncover new alt-EJ players and decipher their mechanisms of action in cancer. Identifying additional components of the alt-EJ pathway and understanding the crosstalk that exists between alt-EJ and other pathways could lead to the discovery of new potential synthetic lethal interactions and as such new potential drug target for cancer treatment (Figure 2B).

In addition, repair of DSBs contribute to the stabilization of damaged replication forks (RFs), that recently emerged as a central process that controls genomic stability and promotes chemoresistance. Characterizing the molecular pathways regulating genomic stability at damaged replication forks in HR-deficient cancers will increase our understanding of the cellular response to replicative stress, and in the same time, potentially allow the identification of new predictors (biomarkers) of chemo- sensitivity/resistance in these tumors (Figure 2B).

Our current project on the characterization of the alternative end joining DNA repair mechanism in cancer has been awarded an ATIP-Avenir and ERC Starting grant (starting date: July 1st 2017).

 

A full list of publications can be found here

Key publications

Year of publication 2016

Zeina Kais, Beatrice Rondinelli, Amie Holmes, Colin O'Leary, David Kozono, Alan D D'Andrea, Raphael Ceccaldi (2016 Jun 7)

FANCD2 Maintains Fork Stability in BRCA1/2-Deficient Tumors and Promotes Alternative End-Joining DNA Repair.

Cell reports : 2488-99 : DOI : 10.1016/j.celrep.2016.05.031

Year of publication 2015

Panagiotis A Konstantinopoulos, Raphael Ceccaldi, Geoffrey I Shapiro, Alan D D'Andrea (2015 Oct 15)

Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer.

Cancer discovery : 1137-54 : DOI : 10.1158/2159-8290.CD-15-0714
Raphael Ceccaldi, Beatrice Rondinelli, Alan D D'Andrea (2015 Oct 7)

Repair Pathway Choices and Consequences at the Double-Strand Break.

Trends in cell biology : 52-64 : DOI : 10.1016/j.tcb.2015.07.009
Raphael Ceccaldi, Jessica C Liu, Ravindra Amunugama, Ildiko Hajdu, Benjamin Primack, Mark I R Petalcorin, Kevin W O'Connor, Panagiotis A Konstantinopoulos, Stephen J Elledge, Simon J Boulton, Timur Yusufzai, Alan D D'Andrea (2015 Feb 3)

Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair.

Nature : 258-62 : DOI : 10.1038/nature14184
All publications