From yeast to humans: Understanding the biology of DNA Damage Response (DDR) kinases

Abstract

The DNA Damage Response (DDR) is a complex network of biological processes that protect cells from accumulating aberrant DNA structures, thereby maintaining genomic stability and, as a consequence, preventing the development of cancer and other diseases. The DDR pathway is coordinated by a signaling cascade mediated by the PI3K-like kinases (PIKK) ATM and ATR and by their downstream kinases CHK2 and CHK1, respectively. Together, these kinases regulate several aspects of the cellular program in response to genomic stress. Much of our understanding of these kinases came from studies performed in the 1990s using yeast as a model organism. The purpose of this review is to present a historical perspective on the discovery of the DDR kinases in yeast and the importance of this model for the identification and functional understanding of their mammalian orthologues. Figure 1 -Timeline for the discovery of DDR kinases in yeast and human. Although the gene encoding S. pombe Chk1 was identified before Dun1, its kinase activity was associated with DDR only in 1996 (Walworth and Bernards, 1996).

In‐depth and 3‐dimensional exploration of the budding yeast phosphoproteome

“…This curation contains measurements for the behavior of over 23,000 phosphosites (Dataset EV7). In budding yeast, DNA damage signaling is mediated by the sensor kinases Mec1 and Tel1 and the downstream checkpoint kinase Rad53 (see recent reviews (Giannattasio & Branzei, 2017; Pardo et al , 2017; Cussiol et al , 2019; Lanz et al , 2019)), while the cyclin‐dependent kinase orders the progression of the budding yeast cell cycle. Phosphopeptides whose abundance is dependent on the action of these kinases have been identified previously (Holt et al , 2009; Bastos de Oliveira et al , 2015), and the behavior of these “substrate” phosphopeptides can be used to track kinase activity (Fig 4A) (Hustedt et al , 2015; Bastos de Oliveira et al , 2018; Lanz et al , 2018).…”

DNA Damage Responses during the Cell Cycle: Insights from Model Organisms and Beyond

“…Two other PIKKs, Protein Kinase DNA-activated catalytic subunit (PRKDC) and Ataxia telangiectasia mutated (ATM), are often recruited to sites of DSBs. PRKDC is notably absent in many model organisms ( Figure 1 ) including S. cerevisiae, S. pombe, C. elegans, Drosophila and A. thaliana [ 46 , 47 , 48 ] (see the sections “Interphase: cNHEJ or HR” and “Emerging model DDR systems”).…”

Crosstalk between the mTOR and DNA Damage Response Pathways in Fission Yeast

“…To avoid the “fixing” of mutations and/or chromosome mis-segregation during mitosis, cells must arrest cell cycle progression and delay mitosis (DNA damage checkpoints) until damaged DNA has been repaired [ 38 ]. While various forms of DNA damage (ranging from base misincorporation and additions to double strand breaks) occur, in S. pombe , Rad3 is the major regulator of the DNA damage response and a member of the PIKK family [ 39 , 40 , 41 , 42 , 43 , 44 ] ( Figure 2 ). Rad3 is a homologue of the mammalian ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR) and Saccharomyces cerevisiae ( S. cerevisiae ) Mec1 proteins [ 42 , 43 ].…”

“…DNA damage checkpoint activation and maintenance, thus, require the dual regulation of Cdc25 and Mik1/ Wee1 activity to effectively inhibit Cdc2 [ 47 ]. Additionally, cells must be able to effectively resume cell cycle progression once DNA repair has been completed, linking DNA damage checkpoint activation and resumption of cell division [ 44 , 48 ]. In general, these pathways are evolutionarily conserved and follow a general pattern of DNA damage detection, signal activation, signal amplification/transmission, and execution.…”