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The CYLD-PARP1 feedback loop regulates DNA damage repair and chemosensitivity in breast cancer cells

Miaomiao Zheng1, Shuo Wang1, Kexin Tang1

  • 1Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Department of Biochemistry and Molecular Biology, College of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, China.

Proceedings of the National Academy of Sciences of the United States of America
|December 31, 2024
PubMed

Insights

Cylindromatosis (CYLD) deubiquitinates Poly(ADP-ribose) polymerase 1 (PARP1), impacting DNA repair in breast cancer. Targeting this CYLD-PARP1 interaction may enhance chemotherapy efficacy.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Poly(ADP-ribose) polymerase 1 (PARP1) is vital for DNA repair and genomic stability.
  • Regulatory mechanisms of PARP1, especially deubiquitination, are not fully understood.

Purpose of the Study:

  • To identify deubiquitinases (DUBs) regulating PARP1 activity.
  • To elucidate the role of CYLD in PARP1 regulation and its implications in breast cancer.

Main Methods:

  • Utilized a DUB library binding screen to identify PARP1-interacting DUBs.
  • Investigated the mechanistic interplay between CYLD and PARP1 at DNA lesions.
  • Assessed the impact of CYLD modulation on DNA repair pathways and drug sensitivity in breast cancer cells.

Main Results:

  • Identified cylindromatosis (CYLD) as a deubiquitinase for PARP1 in breast cancer cells.
  • CYLD cleaves K63-linked polyubiquitin chains on PARP1, reducing its activation.
  • PARP1 PARylates CYLD, enhancing its deubiquitinase activity.
  • CYLD depletion increases base excision repair efficiency and confers resistance to alkylating agents.
  • CYLD overexpression sensitizes breast cancer cells to PARP inhibitors (PARPi).

Conclusions:

  • Established a reciprocal regulatory relationship between CYLD and PARP1 in DNA repair.
  • CYLD deubiquitination of PARP1 is a critical mechanism controlling DNA repair efficiency.
  • The CYLD-PARP1 axis represents a potential therapeutic target for breast cancer chemotherapy.
Keywords:
CYLDPARP1PARylationdeubiquitinationdrug sensitivity

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