Minichromosome Maintenance Proteins: From DNA Replication to the DNA Damage Response

Abstract

The DNA replication machinery is highly conserved from bacteria to eukaryotic cells. Faithful DNA replication is vital for cells to transmit accurate genetic information to the next generation. However, both internal and external DNA damages threaten the intricate DNA replication process, leading to the activation of the DNA damage response (DDR) system. Dysfunctional DNA replication and DDR are a source of genomic instability, causing heritable mutations that drive cancer evolutions. The family of minichromosome maintenance (MCM) proteins plays an important role not only in DNA replication but also in DDR. Here, we will review the current strides of MCM proteins in these integrated processes as well as the acetylation/deacetylation of MCM proteins and the value of MCMs as biomarkers in cancer.

Keywords: DNA damage response (DDR); DNA replication; cell cycle checkpoint; minichromosome maintenance (MCM); origin recognition complex (ORC); pre-replication complex (pre-RC); replication stress.

Figure 1

The domain structures of MCM family proteins. (A) Three domains of MCM family proteins. (B) The domain structures of MCM family proteins: MCM2-10. wHTH stands for the winged helix-turn-helix motif. Please see the text for more details.

Figure 2

Summarizing the relationships between MCMs and DDR. (A) With respect to MCM2–7, known effects on MCM by the ATM/ATR pathway: ATM and ATR phosphorylate MCM2 on Serine 92, ATR phosphorylates MCM2 on Serine 108, cyclinE/Cdk2 phosphorylate MCM3 Threonine 722, Chk1 phosphorylates MCM3 on Serine 205, ATR phosphorylates MCM6 on Serine 13, Rad17 interacts with MCM7, MCM7 is phosphorylated on Serine 121 by cyclinE/Cdk2 and cyclinB/Cdk1. (B) Protein interactions between MCM2–7 and DDR proteins: MCM2 and MCM3 interact with Rad51 and Rad52MCM2/3 and /Rad51 promotes non-HRR repair, ATRIP interacts with MCM7, MCM3 interacts with Rad51 and Rad52; MCM2 interacts with Rad52, 53BP1 interacts with MCM 2/3/5/6. (C) MCM8/9 functions within DDR: MCM8 and MCM9 form a complex and are involved in HRR, MCM8 and MCM9 are involved in interstrand crosslink repair (ICL) repair and functions downstream of BRCA2/Rad51-Fanconi anemia pathways, and HROB recruits MCM8/9 to DNA damage sites. (D) Protein interactions between MCM8/9 and DDR proteins: MCM8IP interacts with MCM8/9, MCM8/9 interacts and directs BRCA1 and Rad51 to protect forks from excessive degradation, MCM9 interacts with mismatched repair (MMR) initiator proteins (MSH3, MSH2, MLH1), and HORMAD1 interacts with MCM8/MCM9. (E) MCM10 knockdown causes an increase in Chk1 and Chk2 expression, DNA breaks. (F) Known protein interactions between MCM10 and DDR proteins: MCM10 interacts with BRCA2 and PALB2.

Figure 2

Summarizing the relationships between MCMs and DDR. (A) With respect to MCM2–7, known effects on MCM by the ATM/ATR pathway: ATM and ATR phosphorylate MCM2 on Serine 92, ATR phosphorylates MCM2 on Serine 108, cyclinE/Cdk2 phosphorylate MCM3 Threonine 722, Chk1 phosphorylates MCM3 on Serine 205, ATR phosphorylates MCM6 on Serine 13, Rad17 interacts with MCM7, MCM7 is phosphorylated on Serine 121 by cyclinE/Cdk2 and cyclinB/Cdk1. (B) Protein interactions between MCM2–7 and DDR proteins: MCM2 and MCM3 interact with Rad51 and Rad52MCM2/3 and /Rad51 promotes non-HRR repair, ATRIP interacts with MCM7, MCM3 interacts with Rad51 and Rad52; MCM2 interacts with Rad52, 53BP1 interacts with MCM 2/3/5/6. (C) MCM8/9 functions within DDR: MCM8 and MCM9 form a complex and are involved in HRR, MCM8 and MCM9 are involved in interstrand crosslink repair (ICL) repair and functions downstream of BRCA2/Rad51-Fanconi anemia pathways, and HROB recruits MCM8/9 to DNA damage sites. (D) Protein interactions between MCM8/9 and DDR proteins: MCM8IP interacts with MCM8/9, MCM8/9 interacts and directs BRCA1 and Rad51 to protect forks from excessive degradation, MCM9 interacts with mismatched repair (MMR) initiator proteins (MSH3, MSH2, MLH1), and HORMAD1 interacts with MCM8/MCM9. (E) MCM10 knockdown causes an increase in Chk1 and Chk2 expression, DNA breaks. (F) Known protein interactions between MCM10 and DDR proteins: MCM10 interacts with BRCA2 and PALB2.