Replicatively senescent cells are arrested in G1 and G2 phases

Abstract

Most human somatic cells do not divide indefinitely but enter a terminal growth arrest termed replicative senescence. Replicatively senescent cells are generally believed to arrest in G1 or G0 stage of the cell cycle. While doing cell cycle analysis on three different lines of normal human fibroblasts we observed that 36-60% of the replicatively senescent cells had 4N DNA content. Only up to 5% of senescent cells had more than one nucleus ruling out the possibility that the 4N cell population were G1-arrested bi-nucleated cells. Furthermore, it is unlikely that the 4N cells are tetraploids, because actively dividing pre-senescent cultures lacked the 8N tetraploid G2 population. Collectively these results suggest that the 4N population consists of G2 arrested cells. The notion that a large fraction of senescent cell population is arrested in G2 is important for understanding the biology of replicative senescence.

Temporally distinct roles of ATM and ROS in genotoxic-stress-dependent induction and maintenance of cellular senescence

“…Treated cells were found to be trapped predominantly in G1 phase (Fig. 2E) and were prevented from entering the S phase due to replication arrest, similar to what has been reported previously (Mao et al, 2012). To confirm that entry into synthesis phase of cell cycle is crucial for BrdU action, we treated cells that had been starved by culturing them in DMEM containing only 0.1% serum with BrdU, and found that senescence induction was not observed, indicating that the quiescent cells are refractory to BrdU incorporation (data not shown).…”

Senescence from G2 arrest, revisited

“…The first paper demonstrated that the presence of a significant fraction of senescent fibroblasts with a 4N DNA content and strongly expressing cyclin D1 is not due to gradual accumulation of bi-nucleate or tetraploid G1 cells in aging cultures, but the consequence of cell cycle exit after G2 arrest. 79 Accumulation of cyclin D1 and E1 was also observed in G2-arrested cells following ectopic induction of p21. 80 More recently, it has been shown that in telomerase-negative cells eroded telomeres elicit DDR predominantly in G2, leading to p53/p21-dependent cell cycle arrest/ exit with 4N DNA content.…”

Geroconversion: irreversible step to cellular senescence

“…Indeed, aging is not just cell cycle arrest. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] In analogy, although cell cycle progression is important in carcinogenesis, we do not define cancer as cell cycle progression. For one, intestinal and bone marrow progenitor cells proliferate faster than tumor cells.…”