WIP1 Contributes to the Adaptation of Fanconi Anemia Cells to DNA Damage as Determined by the Regulatory Network of the Fanconi Anemia and Checkpoint Recovery Pathways.

Alfredo Rodríguez,Cecilia Ayala-Zambrano,Benilde García De Teresa,Leda Torres,Eugenio Azpeitia,Sara Frías,Luis Mendoza,J Jesús Naveja,Ulises Juárez-Figueroa

doi:10.3389/fgene.2019.00411

Alfredo Rodríguez, Cecilia Ayala-Zambrano + Show 7 more

Open Access

https://doi.org/10.3389/fgene.2019.00411

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Abstract

DNA damage adaptation (DDA) allows the division of cells with unrepaired DNA damage. DNA repair deficient cells might take advantage of DDA to survive. The Fanconi anemia (FA) pathway repairs DNA interstrand crosslinks (ICLs), and deficiencies in this pathway cause a fraction of breast and ovarian cancers as well as FA, a chromosome instability syndrome characterized by bone marrow failure and cancer predisposition. FA cells are hypersensitive to ICLs; however, DDA might promote their survival. We present the FA-CHKREC Boolean Network Model, which explores how FA cells might use DDA. The model integrates the FA pathway with the G2 checkpoint and the checkpoint recovery (CHKREC) processes. The G2 checkpoint mediates cell-cycle arrest (CCA) and the CHKREC activates cell-cycle progression (CCP) after resolution of DNA damage. Analysis of the FA-CHKREC network indicates that CHKREC drives DDA in FA cells, ignoring the presence of unrepaired DNA damage and allowing their division. Experimental inhibition of WIP1, a CHKREC component, in FA lymphoblast and cancer cell lines prevented division of FA cells, in agreement with the prediction of the model.

Highlights

Interstrand crosslinks (ICLs) are severe DNA lesions that interfere with essential cellular processes, such as DNA replication and gene transcription
We found that Fanconi anemia (FA) pathway deficient cells might promote damage adaptation (DDA) through several mechanisms, including (1) promotion of an alternative interstrand crosslinks (ICLs) unhooking pathway that enables replication fork collapse and generation of double strand breaks (DSBs), and (2) over-dependence on the checkpoint recovery (CHKREC), which might inactivate the DNA damage repair and checkpoint proteins, ignoring the presence of unrepaired DSBs and promoting cell division
In this study we propose the FA-CHKREC Boolean network model and use it as a tool to suggest hypotheses to explain the imbalance between the checkpoint and CHKREC that generates DDA in FA pathway mutant cells

Summary

Introduction

Interstrand crosslinks (ICLs) are severe DNA lesions that interfere with essential cellular processes, such as DNA replication and gene transcription. ICLs activate the Fanconi anemia (FA) pathway ( known as the FA/BRCA pathway) and the cell cycle checkpoint, which induces cell cycle arrest (CCA) providing time for the restoration of DNA integrity (Giglia-Mari et al, 2011). While the FA pathway combines homologous recombination repair (HRR), translesion synthesis (TLS) and nucleotide excision repair (NER) for restoration of DNA integrity (Ceccaldi et al, 2016b), the checkpoint activation during G2 avoids the inheritance of unrepaired DNA damage (Zhou and Elledge, 2000; Lobrich and Jeggo, 2007). Somatic inactivation of the FA pathway has been identified in breast, ovarian, and pancreatic tumors (Ceccaldi et al, 2016b). Heterozygous females for certain FA pathway mutations, such as BRCA1 and BRCA2, have an increased risk of breast and ovarian cancer (Tung, 2015; Nielsen et al, 2016)

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