A Boolean network model of the double-strand break repair pathway choice
Por:
Ayala-Zambrano, Cecilia, Yuste, Mariana, Frias, Sara, Garcia-de-Teresa, Benilde, Mendoza, Luis, Azpeitia, Eugenio, Rodriguez, Alfredo, Torres, Leda
Publicada:
21 sep 2023
Ahead of Print:
1 ago 2023
Resumen:
Double strand break (DSB) repair is critical to maintaining the
integrity of the genome. DSB repair deficiency underlies multiple
pathologies, including cancer, chromosome instability syndromes, and,
potentially, neurodevelopmental defects. DSB repair is mainly handled by
two pathways: highly accurate homologous recombination (HR), which
requires a sister chromatid for template-based repair, limited to S/G2
phases of the cell cycle, and canonical non-homologous end joining
(c-NHEJ), available throughout the cell cycle in which minimum homology
is sufficient for highly efficient yet error-prone repair. Some
circumstances, such as cancer, require alternative highly mutagenic DSB
repair pathways like microhomology-mediated end-joining (MMEJ) and
single-strand annealing (SSA), which are triggered to attend to DNA
damage. These non-canonical repair alternatives are emerging as
prominent drivers of resistance in drug-based tumor therapies. Multiple
DSB repair options require tight inter-pathway regulation to prevent
unscheduled activities. In addition to this complexity, epigenetic
modifications of the histones surrounding the DSB region are emerging as
critical regulators of the DSB repair pathway choice. Modeling
approaches to understanding DSBs repair pathway choice are advantageous
to perform simulations and generate predictions on previously
uncharacterized aspects of DSBs response. In this work, we present a
Boolean network model of the DSB repair pathway choice that incorporates
the knowledge, into a dynamic system, of the inter-pathways regulation
involved in DSB repair, i.e., HR, c-NHEJ, SSA, and MMEJ. Our model
recapitulates the well-characterized HR activity observed in wild-type
cells in response to DSBs. It also recovers clinically relevant
behaviors of BRCA1/FANCS mutants, and their corresponding drug
resistance mechanisms ascribed to DNA repair gain-of-function pathogenic
variants. Since epigenetic modifiers are dynamic and possible druggable
targets, we incorporated them into our model to better characterize
their involvement in DSB repair. Our model predicted that loss of the
TIP60 complex and its corresponding histone acetylation activity leads
to activation of SSA in response to DSBs. Our experimental validation
showed that TIP60 effectively prevents activation of RAD52, a key SSA
executor, and confirms the suitable use of Boolean network modeling for
understanding DNA DSB repair.
Filiaciones:
Ayala-Zambrano, Cecilia:
Laboratorio de Citogenética, Instituto Nacional de Pediatría, Ciudad de México, 04530, Mexico
Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Ciudad de México, 04510, Mexico
Instituto Nacional de Pediatría, Ciudad de México, 04530, Mexico
Inst Nacl Pediat, Lab Citogenet, Ciudad De Mexico 04530, Mexico
Univ Nacl Autonoma Mexico, Posgrad Ciencias Biol, Ciudad De Mexico, Mexico
Yuste, Mariana:
Centro de Ciencias Matemáticas, Universidad Nacionál Autónoma de México, Morelia, Mexico
Univ Nacl Autonoma Mexico, Ctr Ciencias Matemat, Morelia, Mexico
Frias, Sara:
Laboratorio de Citogenética, Instituto Nacional de Pediatría, Ciudad de México, 04530, Mexico
Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Apartado Postal 70228, Ciudad de México, 04510, Mexico
Instituto Nacional de Pediatría, Ciudad de México, 04530, Mexico
Inst Nacl Pediat, Lab Citogenet, Ciudad De Mexico 04530, Mexico
Univ Nacl Autonoma Mexico, Dept Med Genomica & Toxicol Ambiental, Inst Invest Biomed, Apartado Postal 70228, Ciudad De Mexico 04510, Mexico
Garcia-de-Teresa, Benilde:
Laboratorio de Citogenética, Instituto Nacional de Pediatría, Ciudad de México, 04530, Mexico
Instituto Nacional de Pediatría, Ciudad de México, 04530, Mexico
Inst Nacl Pediat, Lab Citogenet, Ciudad De Mexico 04530, Mexico
Mendoza, Luis:
Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Apartado Postal 70228, Ciudad de México, 04510, Mexico
Univ Nacl Autonoma Mexico, Dept Biol Mol & Biotecnol, Inst Invest Biomed, Apartado Postal 70228, Ciudad De Mexico 04510, Mexico
Azpeitia, Eugenio:
Centro de Ciencias Matemáticas, Universidad Nacionál Autónoma de México, Morelia, Mexico
Univ Nacl Autonoma Mexico, Ctr Ciencias Matemat, Morelia, Mexico
Rodriguez, Alfredo:
Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Apartado Postal 70228, Ciudad de México, 04510, Mexico
Instituto Nacional de Pediatría, Ciudad de México, 04530, Mexico
Univ Nacl Autonoma Mexico, Dept Med Genomica & Toxicol Ambiental, Inst Invest Biomed, Apartado Postal 70228, Ciudad De Mexico 04510, Mexico
Inst Nacl Pediat, Ciudad De Mexico 04530, Mexico
Torres, Leda:
Laboratorio de Citogenética, Instituto Nacional de Pediatría, Ciudad de México, 04530, Mexico
Instituto Nacional de Pediatría, Ciudad de México, 04530, Mexico
Inst Nacl Pediat, Lab Citogenet, Ciudad De Mexico 04530, Mexico
hybrid, Hybrid Gold
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