Normal mammalian cells negatively regulate telomere length by telomere trimming

Area of Science:

• Genetics
• Cell Biology
• Molecular Biology

Background:

• Telomeres protect chromosome ends but shorten with replication.
• Exogenous telomerase can lead to over-lengthened telomeres in cancer cells.
• Telomere shortening can occur via a process generating telomeric DNA circles (t-circles).

Purpose of the Study:

• To investigate the occurrence and mechanism of telomere trimming in normal mammalian cells.
• To determine if telomere trimming is a general mechanism for telomere length regulation.
• To explore the role of homologous recombination (HR) in telomere trimming.

Main Methods:

• Analysis of t-circle formation in human cancer cells, male germline cells, and stimulated lymphocytes.
• Investigation of t-circle presence in mouse tissues.
• Examination of the involvement of the XRCC3 HR protein in the telomere trimming process.

Main Results:

• Telomere trimming and t-circle formation were observed in human male germline cells and stimulated lymphocytes.
• Abundant t-circles were found in mouse tissues, indicating conserved telomere trimming.
• The mechanism involves the XRCC3 HR protein and generates single-stranded C-rich telomeric DNA.

Conclusions:

• Telomere trimming is a rapid, negative telomere length control mechanism in normal mammalian cells, complementing gradual attrition.
• This HR-mediated process likely prevents excessive telomere lengthening, particularly in germline and somatic cells.
• Telomere trimming represents an additional factor in telomere length homeostasis, balancing lengthening and shortening.