Roles of Claspin in regulation of DNA replication, replication stress responses and oncogenesis in human cells

Abstract

Human cells need to cope with the stalling of DNA replication to complete replication of the entire genome to minimize genome instability. They respond to “replication stress” by activating the conserved ATR-Claspin-Chk1 replication checkpoint pathway. The stalled replication fork is detected and stabilized by the checkpoint proteins to prevent disintegration of the replication fork, to remove the lesion or problems that are causing fork block, and to facilitate the continuation of fork progression. Claspin, a factor conserved from yeasts to human, plays a crucial role as a mediator that transmits the replication fork arrest signal from the sensor kinase, ataxia telangiectasia and Rad3-related (ATR), to the effector kinase, Checkpoint kinase 1 (Chk1). Claspin interacts with multiple kinases and replication factors and facilitates efficient replication fork progression and initiation during the normal course of DNA replication as well. It interacts with Cdc7 kinase through the acidic patch segment near the C-terminus and this interaction is critical for efficient phosphorylation of Mcm in non-cancer cells and also for checkpoint activation. Phosphorylation of Claspin by Cdc7, recruited to the acidic patch, regulates the conformation of Claspin through affecting the intramolecular interaction between the N- and C-terminal segments of Claspin. Abundance of Claspin is regulated at both mRNA and protein levels (post-transcriptional regulation and protein stability) and affects the extent of replication checkpoint. In this article, we will discuss how the ATR-Claspin-Chk1 regulates normal and stressed DNA replication and provide insight into the therapeutic potential of targeting replication checkpoint for efficient cancer cell death.

Immunohistochemical Expression of Claspin and TopBP1 in Prostatic Adenocarcinoma: Correlation with Clinicopathological Parameters and Prognostic Significance

“…Claspin is a multifunctional crucial protein that are essential for the maintenance of genome stability (5) . Claspin has been constituted as a promising therapeutic target in neoplasms, specifically for chemo and radio-sensitization (20) .…”

“…In contrast to its function in DNA replication, Claspin contains DNA repair pathways like repair of nucleotide excision (21) , homologous recombination and mismatch repair (22) . Therefore, this dual effect of Claspin in carcinogenesis require further investigation (5) .…”

“…A cornerstone of neoplastic transformation is instability of the genome that occurs due to deficiencies in maintenance mechanisms of genome integrity, including the checkpoints of the cell cycle, DNA repair and DNA proliferation control. Accordingly, a mainstay of cancer research is genome protective mechanisms investigations (5) . Throughout proliferation stress, to keep the integrity of the genome, the proliferation checkpoint pathways ATR-Claspin-Chk1 is triggered (6) .…”

Claspin-dependent and -independent Chk1 activation by a panel of biological stresses

“…We have reported novel functions and mechanisms of Claspin actions in replication initiation and in replication checkpoint activation [3-4, 45-46]. More recently, we reported that Claspin regulates growth restart from serum starvation by activating the PI3K-PDK1-mTOR pathway [45].…”

“…Claspin is involved in the ATR-Chk1 signaling axis in the replication stress response as an essential mediator [3][4][5][6][7].…”