Sex-specific differences in DNA double-strand break repair of cycling human lymphocytes during aging.

Melanie Rall-Scharpf,Michael Milyavsky,Thomas W.P Friedl,Michael Denkinger,Lisa Wiesmüller,Shahar Biechonski

doi:10.18632/aging.203519

Melanie Rall-Scharpf, Michael Milyavsky + Show 4 more

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https://doi.org/10.18632/aging.203519

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Abstract

The gender gap in life expectancy and cancer incidence suggests differences in the aging process between the sexes. Genomic instability has been recognized as a key factor in aging, but little is known about sex-specific differences. Therefore, we analyzed DNA double-strand break (DSB) repair in cycling human peripheral blood lymphocytes (PBL) from male and female donors of different age. Reporter-based DSB repair analyses revealed differential regulation of pathway usage in PBL from male and female donors with age: Non-homologous end joining (NHEJ) was inversely regulated in men and women; the activity of pathways requiring end processing and strand annealing steps such as microhomology-mediated end joining (MMEJ) declined with age in women but not in men. Screening candidate proteins identified the NHEJ protein KU70 as well as the end resection regulatory factors ATM and BLM showing reduced expression during aging in women. Consistently, the regulatory factor BLM contributed to the MMEJ proficiency in young but not in old women as demonstrated by knockdown analysis. In conclusion, we show that DSB repair is subject to changes upon aging and age-related changes in DSB repair are distinct in men and women.

Highlights

Aging is an inherently complex process, our understanding of which is limited
The activities of specific double-strand break (DSB) repair pathways change in peripheral blood lymphocytes (PBL) with age in a sex-dependent manner
DSB repair pathway usage was analyzed in ex vivo cultured, cycling lymphocytes isolated from peripheral blood of young voluntary donors aged between >17 and 26 years and from elderly voluntary donors older than 60 years (Table 1)

Summary

Introduction

Aging is an inherently complex process, our understanding of which is limited. Two phenotypic aspects of this complexity are the gender gap in life expectancy of on average 4 years (WHO, 2019), as well as varying incidences of age-associated diseases, such as cardiovascular, neurodegenerative, autoimmune and malignant diseases [1], both suggesting differences in the aging process between the sexes.Genomic instability has been defined as one of the hallmarks of aging [2], as it is accompanied by an accumulation of genetic alterations including point mutations, large chromosomal rearrangements and attrition of telomeres [3]. Aging is an inherently complex process, our understanding of which is limited. A higher load of DNA damage can be observed in different primitive and mature cell types of aged organisms including humans [3,4,5]. During S- and G2phase MMEJ, single-strand annealing (SSA) and homologous recombination (HR), which require DNA end resection to generate 3’ single-stranded DNA www.aging-us.com overhangs for the search of homologies, are favored [9]. Initial end resection by the MRE11-RAD50NBS1-CtIP complex is sufficient for MMEJ [9]. While HR allows error-free repair by copying sequence information from the homologous sister chromatid, SSA and MMEJ involve annealing of repeats within the two resected DNA strands resulting in loss of the sequence in between

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