2. Academic Validation
  3. The importance of DNAPKcs for blunt DNA end joining is magnified when XLF is weakened

The importance of DNAPKcs for blunt DNA end joining is magnified when XLF is weakened

  • Nat Commun. 2022 Jun 27;13(1):3662. doi: 10.1038/s41467-022-31365-6.
Metztli Cisneros-Aguirre 1 2,  Felicia Wednesday Lopezcolorado 1,  Linda Jillianne Tsai 1 2,  Ragini Bhargava 1 2 3,  Jeremy M Stark 4 5
Affiliations

Affiliations

  • 1 Department of Cancer Genetics and Epigenetics, Beckman Research Institute of the City of Hope, 1500 E Duarte Rd, Duarte, CA 91010, USA.
  • 2 Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, 1500 E Duarte Rd, Duarte, CA 91010, USA.
  • 3 Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
  • 4 Department of Cancer Genetics and Epigenetics, Beckman Research Institute of the City of Hope, 1500 E Duarte Rd, Duarte, CA 91010, USA. jstark@coh.org.
  • 5 Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, 1500 E Duarte Rd, Duarte, CA 91010, USA. jstark@coh.org.
PMID: 35760797 DOI: 10.1038/s41467-022-31365-6
Abstract

Canonical non-homologous end joining (C-NHEJ) factors can assemble into a long-range (LR) complex with DNA ends relatively far apart that contains DNAPKcs, XLF, XRCC4, LIG4, and the KU heterodimer and a short-range (SR) complex lacking DNAPKcs that has the ends positioned for ligation. Since the SR complex can form de novo, the role of the LR complex (i.e., DNAPKcs) for chromosomal EJ is unclear. We have examined EJ of chromosomal blunt DNA double-strand breaks (DSBs), and found that DNAPKcs is significantly less important than XLF for such EJ. However, weakening XLF via disrupting interaction interfaces causes a marked requirement for DNAPKcs, its kinase activity, and its ABCDE-cluster autophosphorylation sites for blunt DSB EJ. In contrast, other aspects of genome maintenance are sensitive to DNAPKcs kinase inhibition in a manner that is not further enhanced by XLF loss (i.e., suppression of homology-directed repair and structural variants, and IR-resistance). We suggest that DNAPKcs is required to position a weakened XLF in an LR complex that can transition into a functional SR complex for blunt DSB EJ, but also has distinct functions for other aspects of genome maintenance.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-101570
    99.70%, DNA-PK抑制剂
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