DNA interstrand crosslink lesions and blood disorder

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The Marseille Cancer Research Center celebrates its 50th anniversary ! -

Lachaud team is part of the Genome Integrity department

Our laboratory integrates multidisciplinary approaches by bringing together the expertise of biologists, pathologists, clinicians, and chemists. This collaboration aims to address the shortage of appropriate tools.

DNA interstrand crosslinks (ICLs) is one of the most toxic lesions. It covalently binds both strands of the DNA, thus blocking the essential cellular processes that require translocation along the DNA, namely DNA replication and transcription. In actively dividing cells, the replicative machinery will collide with an ICL, and this is thought to be a prevalent mechanism for sensing these lesions. If not repair, the absence of DNA replication will lead to cell death. Many ICLs inducing agent are currently used in chemotherapy. This includes cisplatin, psoralen and melphalan. The efficiency of these drugs in targeting cancer is not equivalent. This difference is probably due to a difference in how the lesions are detected and repair. In order to understand the differences of drugs efficiency and improve chemotherapy further studies are necessary to quantify the lesions and identify mechanism of repair in cells and in vivo.

Additionally, excessive exposure to ICLs drastically increases the frequency of leukaemia. Indeed, leukaemia is one of the main side effects observed in patients after treatment with ICL based chemotherapy. Leukaemia onset generally occurs around 5 years after the beginning of the chemotherapy, and is often preceded by anaemia. The prognosis for patient who develops leukaemia following chemotherapy is poor, making early detection essential. Therefore, identification of patient with risk has become essential.

Our lab currently combines multidisciplinary approaches that will combine the work of biologists, pathologists, clinicians and chemists in order to overcome the lack of suitable tools and achieve 3 main projects.

Research projects
Detection of ICL lesions to characterize ICL repair

The integrity of human DNA is constantly challenged by highly reactive molecules. DNA inter-strand crosslinks (ICLs) are toxic lesions that covalently link the two DNA strands and rapidly affect replicating cells such as cancer or stem cells. For example, exposure to various ICL inducing drugs or defects in ICL repair pathways profoundly impact cells and can induce various type of diseases. We aim to understand how ICLs are repaired in human cells in order to have a better knowledge about the relation between the lesions, how they are repaired and why they lead to diseases. This proposal is based on newly synthesized drugs that allow to monitor the lesions in cells. Using these new drugs, we will overcome the lack of suitable tools and decipher ICLs repair in mammals. We will focus on analyzing the spatial distribution of the lesions/repair in cells and on characterizing the interplay between different ICLs repair pathway.

Role of FAN1 in cancer resistance to chemotherapy

Breast cancer is the most common malignancy among women worldwide, accounting for about 25% of all new cancer cases in women, and it is the fifth leading cause of cancer death among women. Despite the high incidence, the mortality rate is low (15%), mostly because of early diagnosis and the increasing use of adjuvant therapy. Adjuvant chemotherapy for breast cancer includes the incorporation of taxol (paclitaxel and docetaxel) into anthracyclines and alkylating agents-based treatment. These novel therapeutic strategies have resulted into a considerable improvement of breast cancer survival, but also into an increase of therapy-related AML and myelodisplastic syndromes (MDS). The term “therapy-related” leukaemia (t-AML) is based on patient’s history of exposure to cytotoxic agents. In this context, it is urgent to develop refine strategy to increase the efficiency of adjuvant chemotherapy by reducing drug concentration and reduce frequency of t-AML. We are currently characterizing the role of the protein FAN1 in mediating resistance of breast cancer to chemotherapy.

Roles of UFM1 in hematopoietic cells

UFM1 is the most recently identified Ub-like proteins. Despite its discovery more than a decade ago, its biological functions and working mechanism remains poorly understood. Recent genetics studies based on mouse models provide evidence for the indispensable role of the UFM1 modification in erythroid development. Loss of UFM1 modification blocked autophagy degradation, increased mitochondrial mass and reactive oxygen species (ROS), and led to DNA damage response, p53 activation and enhanced cell death of hematopoietic cells. Interestingly the UFM1 pathway is also essential for the survival of 14 different cell models of Acute myeloid leukemia (AMLs). The involvement of this pathway in more than one biological process, suggest the existence of many UFM1 targets. However, only one protein modified by UFM1 have been identified and explain the relation between UFM1 and breast cancer development. In order to understand the relation between UFM1 and AML, we have used novel proteomic approaches to identify new targeted proteins. We now aim to decipher the roles of these new target in hematopoietic cells.