Single-stranded DNA-binding protein hSSB1 is critical for genomic stability

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• Single-strand DNA-binding proteins (SSBs) are vital for DNA replication, repair, and recombination.
• Replication protein A (RPA) is the primary eukaryotic SSB, a heterotrimer.
• A second human SSB, hSSB1, with archaeal SSB-like organization, is identified.

Purpose of the Study:

• To characterize the function and regulation of the newly identified human SSB1 (hSSB1).
• To investigate hSSB1's role in the DNA damage response pathway, particularly concerning DNA double-strand breaks (DSBs).

Main Methods:

• Investigated hSSB1 phosphorylation by ATM kinase in response to DSBs.
• Observed hSSB1 localization and foci formation in response to DNA damage.
• Assessed the impact of hSSB1 depletion on cellular responses to ionizing radiation and DSBs.

Main Results:

• ATM kinase phosphorylates hSSB1 upon DSB induction, stabilizing the protein.
• hSSB1 accumulates in the nucleus and forms foci, co-localizing with repair proteins, independent of cell cycle phase.
• hSSB1 depletion leads to defective DNA damage response, ATM activation, increased radiosensitivity, and genomic instability.

Conclusions:

• hSSB1 is a critical component of the cellular DNA damage response, distinct from RPA.
• Phosphorylation of hSSB1 by ATM is essential for its stabilization and function in DSB repair.
• hSSB1 deficiency impairs DNA repair capacity and checkpoint activation, highlighting its significance in maintaining genomic integrity.