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ML216 Prevents DNA Damage-Induced Senescence by Modulating DBC1-BLM Interaction

Feng Cui1, Xueying Han1, Xiaoqian Zhang1

  • 1State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.

Cells
|January 8, 2023
PubMed

Insights

DNA damage triggers cell senescence, but DBC1 protein prevents this by protecting BLM from degradation. The compound ML216 enhances this protective interaction, suppressing senescence and improving lung function in mice.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Aging Research

Background:

  • DNA damage is a known inducer of cellular senescence and apoptosis.
  • The precise mechanisms by which DNA-damaged cells transition to senescence are not fully understood.
  • The role of DBC1 (Deleted in Breast Cancer 1) and BLM (Bloom syndrome helicase) in this process requires further elucidation.

Purpose of the Study:

  • To investigate the role of DBC1 in regulating senescence following DNA damage.
  • To explore the interaction between DBC1, BLM, and the process of senescence.
  • To evaluate the therapeutic potential of ML216 in mitigating senescence and related conditions.

Main Methods:

  • Utilized DBC1-deficient cells to assess senescence and apoptosis levels after DNA damage.
  • Investigated the degradation of BLM protein during DNA damage.
  • Examined the effect of ML216 on DBC1-BLM interaction and BLM stability.
  • Assessed pulmonary function and levels of senescence and fibrosis in aged mice and a bleomycin-induced pulmonary fibrosis model.

Main Results:

  • DNA damage induced higher levels of senescence in DBC1-deficient cells compared to apoptosis.
  • BLM protein degradation was observed during DNA damage, correlating with p21 expression and senescence.
  • DBC1 was found to bind and protect BLM from degradation, thereby suppressing senescence.
  • ML216 was shown to promote the DBC1-BLM interaction, preserving BLM and suppressing senescence.
  • ML216 treatment improved pulmonary function and reduced senescence and fibrosis in mouse models.

Conclusions:

  • DBC1-mediated protection of BLM from degradation is a key mechanism preventing DNA-damaged cells from entering senescence.
  • ML216 enhances this protective mechanism, offering a potential therapeutic strategy for senescence-related diseases.
  • Targeting the DBC1-BLM interaction with ML216 shows promise for treating conditions like idiopathic pulmonary fibrosis.
Keywords:
BLMDBC1ML216fibrosissenescence

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