Comprehensive analysis of DNA replication timing across 184 cell lines suggests a role forMCM10in replication timing regulation

Abstract

Cellular proliferation depends on the accurate and timely replication of the genome. Several genetic diseases are caused by mutations in key DNA replication genes; however, it remains unclear whether these genes influence the normal program of DNA replication timing. Similarly, the factors that regulate DNA replication dynamics are poorly understood. To systematically identify trans-acting modulators of replication timing, we profiled replication in 184 cell lines from three cell types, encompassing 60 different gene knockouts or genetic diseases. Through a rigorous approach that considers the background variability of replication timing, we concluded that most samples displayed normal replication timing. However, mutations in two genes showed consistently abnormal replication timing. The first gene was RIF1, a known modulator of replication timing. The second was MCM10, a highly conserved member of the pre-replication complex. Cells from a single patient carrying MCM10 mutations demonstrated replication timing variability comprising 46% of the genome and at different locations than RIF1 knockouts. Replication timing alterations in the mutated MCM10 cells were predominantly comprised of replication delays and initiation site gains and losses. Taken together, this study demonstrates the remarkable robustness of the human replication timing program and reveals MCM10 as a novel candidate modulator of DNA replication timing.

Identification and comprehensive analysis of circRNA–miRNA–mRNA regulatory networks in osteoarthritis

“…In chondrocytes, upregulation of CDC20 and TOP2A might be an indication of insufficient compensatory cartilage and bone regeneration capacity in response to the destruction of cartilage and subchondral bone. Furthermore, MCM10, a highly conserved pre-replication complex, was recently reported to be a modulator of DNA replication timing ( 20 ), suggesting that it plays a potential regulatory role in chondrocyte survival in OA at a deeper genetic level. In addition, another important aspect of OA is the synovial change ( 21 ).…”

Over-Activation of Minichromosome Maintenance Protein 10 Promotes Genomic Instability in Early Stages of Breast Cancer

“…A crucial part of cell proliferation is the replication of DNA that occurs during S phase of the cell cycle and is recognized as a vital biological activity for preserving the stability and integrity of the genome. Recent study into the regulation of replication timing has demonstrated that MCM10 mutations are associated to significant replication timing variations [3]. In addition, MCM10 has also been shown to interact with ssDNA and various critical DNA replication proteins including CDC45, MCM2-7, DNA polymerase, PCNA, and GINS [7][8][9][10][11], all of which are required for accurate cell replication and proliferation.…”

“…A central part of cell proliferation is the replication of DNA that happens during S phase of the cell cycle. Recent research into the regulation of replication timing has found that MCM10 mutations are linked to extensive replication timing variations [3]. It has been reported that cells from a single patient with MCM10 mutations showed replication time variability in 46 percent of the genome, compared to RIF1 knockdown (a known modulator of replication timing) [3].…”

“…Recent research into the regulation of replication timing has found that MCM10 mutations are linked to extensive replication timing variations [3]. It has been reported that cells from a single patient with MCM10 mutations showed replication time variability in 46 percent of the genome, compared to RIF1 knockdown (a known modulator of replication timing) [3]. In addition, MCM10 has been shown to play an important role in DNA unwinding [10].…”

“…Cell proliferation is a crucial element of development that is disrupted in many malignancies. The replication of DNA, which occurs during the S phase of the cell cycle, is a critical component of cell proliferation [3]. A major event in the DNA replication is the conversion of inactive Pre-replication complex (RC) to active RC by linking CMG helicase complex [4] to DNA polymerase.…”