Synthetic lethality between DNA repair factors Xlf and Paxx is rescued by inactivation of Trp53

Sergio Castañeda-Zegarra; Mengtan Xing; Raquel Gago-Fuentes; Siri Sæterstad; Valentyn Oksenych

doi:10.1016/j.dnarep.2018.12.002

Synthetic lethality between DNA repair factors Xlf and Paxx is rescued by inactivation of Trp53

DNA Repair (Amst). 2019 Jan:73:164-169. doi: 10.1016/j.dnarep.2018.12.002. Epub 2018 Dec 16.

Authors

Sergio Castañeda-Zegarra¹, Mengtan Xing², Raquel Gago-Fuentes², Siri Sæterstad², Valentyn Oksenych³

Affiliations

¹ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Laboratory Center, Erling Skjalgssons gate 1, 7491, Trondheim, Norway; St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250 Sluppen, 7006, Trondheim, Norway; Department of Biomedicine, University of Bergen, Bergen, Norway.
² Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Laboratory Center, Erling Skjalgssons gate 1, 7491, Trondheim, Norway; St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250 Sluppen, 7006, Trondheim, Norway.
³ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Laboratory Center, Erling Skjalgssons gate 1, 7491, Trondheim, Norway; St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250 Sluppen, 7006, Trondheim, Norway; Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden. Electronic address: valentyn.oksenych@ntnu.no.

PMID: 30579708
DOI: 10.1016/j.dnarep.2018.12.002

Abstract

Non-homologous end joining (NHEJ) is a DNA repair pathway that senses, processes and ligates DNA double-strand breaks (DSBs) throughout the cell cycle. During NHEJ, core Ku70 and Ku80 subunits bind DSBs as a heterodimer and promote further recruitment of accessory factors (e.g., PAXX, Mri, DNA-PKcs, Artemis) and downstream core subunits XRCC4 and DNA ligase 4 (Lig4). Inactivation of Ku70 or Ku80 genes in mice results in immunodeficiency and high levels of genomic instability; deletion of individual Dna-pkcs, Xlf, Paxx or Mri genes results in viable mice with no or modest DNA repair defects. However, combined inactivation of either Xlf and Dna-pkcs, or Xlf and Paxx, or Xlf and Mri, leads to synthetic lethality in mice, which correlates with increased levels of apoptosis in the central nervous system. Here, we demonstrated that inactivation of pro-apoptotic factor Trp53 rescues embryonic lethality of Xlf^-/-Paxx^-/- and Xlf^-/-Dna-pkcs^-/- double knockout mice. Moreover, combined inactivation of Paxx and Dna-pkcs results in live-born fertile Paxx^-/-Dna-pkcs^-/- mice indistinguishable from Dna-pkcs^-/- knockout controls.

Keywords: B lymphocyte; Cernunnos; Genetic interaction; SCID; Synthetic lethality.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
DNA Repair Enzymes / genetics
DNA Repair*
DNA-Activated Protein Kinase / deficiency
DNA-Activated Protein Kinase / genetics
DNA-Binding Proteins / deficiency
DNA-Binding Proteins / genetics*
Gene Knockout Techniques
Gene Silencing*
Humans
Mice
Nuclear Proteins / deficiency
Nuclear Proteins / genetics
Synthetic Lethal Mutations*
Tumor Suppressor Protein p53 / deficiency*
Tumor Suppressor Protein p53 / genetics*

Substances

DNA-Binding Proteins
NHEJ1 protein, human
Nuclear Proteins
PAXX protein, human
Tumor Suppressor Protein p53
XLF protein, mouse
DNA-Activated Protein Kinase
Prkdc protein, mouse
DNA Repair Enzymes