Academic journal article Genetics

The Anaphase Promoting Complex Regulates Yeast Lifespan and rDNA Stability by Targeting Fob1 for Degradation

Academic journal article Genetics

The Anaphase Promoting Complex Regulates Yeast Lifespan and rDNA Stability by Targeting Fob1 for Degradation

Article excerpt

THE anaphase promoting complex (APC) is a ubiquitin- protein ligase (E3) that is conserved from yeast to hu- mans (Harper et al. 2002; Passmore 2004; Barford 2011; McLean et al. 2011). The APC in yeast is composed of 13 core subunits that interact with the cell-cycle-specific sub- strate-binding adaptors Cdc20 or Cdh1. Eight of the 13 yeast APC subunits are essential, with conditional alleles resulting in cell cycle arrest at the anaphase/metaphase junction (Zachariae and Nasmyth 1999). The APC is required for pro- gression through mitosis and maintenance of G1, functions carried out through the targeted degradation of protein sub- strates that block sister chromatid separation, and exit from mitosis. The list of APC substrates in yeast continues to grow (Qiao et al. 2010; Ostapenko et al. 2012; Ferguson et al. 2013).

The list of cellular functions that involve the APC also continues to grow. These functions include maintenance of genomic stability and control of chromatin metabolism. Several reports demonstrate that APC mutants result in loss of chromosomes and plasmids at accelerated rates (Hartwell and Smith 1985; Palmer et al. 1990; Harkness et al. 2002) and lack the ability to effectively assemble chromatin in vitro, as well as properly regulate histone post-translational mod- ifications (Harkness et al. 2002, 2005; Arnason et al. 2005; Harkness 2005; Turner et al. 2010; Islam et al. 2011). The compilation of defects observed in APC mutants manifest asreducedlifespaninyeastandmice(Bakeret al. 2004; Harkness et al. 2004). The yeast FOXO family members Fkh1 and Fkh2 may play a role in APC-dependent lifespan regulation. The yeast APC appears to respond to signals from Fkh1 and Fkh2 to regulate yeast replicative and chronological lifespan (RLS and CLS, respectively), as well as stress response (Postnikoff et al. 2012). The Fkh proteins drive the expression of histones (Zhu et al. 2000), and when histone metabolism is defective, reduced yeast and worm lifespan results (Dang et al. 2009; Feser et al. 2010; Greer et al. 2011; Han and Brunet 2012). Consistent with a role for the APC in histone metabo- lism and lifespan, human cancer cells are continually being described that express aberrant APC activity (reviewed in Wäsch et al. 2010; Smolders and Teodoro 2011; Chan et al. 2012; Wang et al. 2013). A notable example of this is securin, a major APC substrate found elevated in many cancers that often serves as a prognostic marker of cancer recurrence (Smith et al. 2010; Lewy et al. 2012). Cancer and reduced lifespan are both tightly linked to genomic instability (McMur- ray and Gottschling 2004; Seviour and Lin 2010). In the work presented here, we investigate a specific molecular longevity network regulated by the APC.

Molecular mechanisms involved in determining lifespan in yeast have been heavily studied, with Fob1 being identified as an important player (Sinclair and Guarente 1997; Defossez et al. 1999; Zuin et al. 2010; Kobayashi 2011a; Pan 2011). Fob1 binds the replication fork barrier site (RFB), a specific sequence within rDNA tandem repeats (Mohanty and Bastia 2004), and unidirectionally blocks and stalls DNA replication forks (Kobayashi and Horiuchi 1996; Kobayashi et al. 1998). The stalled replication machinery can result in double- stranded DNA breaks (DSBs). Due to the repeated structure of rDNA, homologous DNA repair of rDNA DSBs can result in unequal sister chromatid exchange (USCE) generating sub- stantial genomic instability within the rDNA region (Sinclair et al. 1997; Kobayashi et al. 1998; Ide et al. 2010). DSBs, resulting from stalled DNA replication forks, and USCE within the rDNA region, may be a conserved process (Mohanty et al. 2009; Ganley et al. 2009).

In contrast to its role in rDNA destabilization, the Fob1 protein also anchors genomic stabilizing factors such as rDNA-specific cohesins, condensins, and Sir2 within the nu- cleolus via interaction with the RENT (regulators of nucleolar silencing and telophase exit) complex (Straight et al. …

Search by... Author
Show... All Results Primary Sources Peer-reviewed

Oops!

An unknown error has occurred. Please click the button below to reload the page. If the problem persists, please try again in a little while.