Involvement of DNA Damage Response via the Ccndbp1-Atm-Chk2 Pathway in Mice with Dextran-Sodium-Sulfate-Induced...

Area of Science:

• Molecular Biology
• Immunology
• Gastroenterology

Background:

• The dextran sodium sulfate (DSS)-induced colitis mouse model is crucial for studying human colitis.
• The mechanism involves double-strand deoxyribonucleic acid (DNA) damage, but the role of the ataxia telangiectasia mutated (Atm)-checkpoint kinase 2 (Chk2) pathway is unclear.
• Cyclin D1-binding protein 1 (Ccndbp1) was recently identified as an activator of the DNA damage response.

Purpose of the Study:

• To investigate the role of Ccndbp1 and the Atm-Chk2 pathway in DSS-induced colitis.
• To evaluate the impact of Ccndbp1 deficiency on colitis severity and associated molecular changes.

Main Methods:

• Induction of colitis in wild-type and Ccndbp1-knockout mice using DSS.
• Assessment of clinical and histological parameters: colon length, disease activity index, and histological scores.
• Evaluation of Atm-Chk2 pathway activation through phosphorylation.
• Quantification of apoptosis using TdT-mediated dUTP-biotin nick end labeling (TUNEL) and cleaved caspase-3 staining.

Main Results:

• DSS-induced colitis led to distal colon inflammation, Atm and Chk2 phosphorylation, increased apoptosis, and worsened disease activity.
• These pathological changes, including colon shortening and elevated histological scores, were significantly reduced in Ccndbp1-knockout mice.
• Ccndbp1 deficiency ameliorated DSS-induced inflammation and apoptosis in the colon.

Conclusions:

• Ccndbp1 plays a significant role in activating the Atm-Chk2 DNA damage response pathway during DSS-induced colitis.
• This activation contributes to colon inflammation and mucosal cell apoptosis.
• Targeting Ccndbp1 may offer a novel therapeutic strategy for managing colitis.