Molecular Mechanism Of SOSS1 Complex Assembly,ssDNA Recognition And SOSS1/INTS6 Interaction

The genome constantly encounters a variety of endogenous and exogenous DNA damaging agents,which will induce genome instability and diseases.If not properly repaired,the damaged DNA will affect the DNA-related metabolic processes such as DNA replication or transcription error.The DNA damage usually involves base substitution,single-stranded and double-stranded breaks,DNA-protein cross-links,and abasic sites,leading to genetic mutations or chromosomal aberrations.DNA double strand breaks(DSBs)are among the most cytotoxic events.In eukaryotes,there are two main DSB repair pathways,i.e.,nonhomologous end joining(NHEJ)and homologous recombination(HR).NHEJ repair occurs throughout the cell cycle,whereas HR repair occurs primarily in the S or G2 phase.At the beginning of homologous recombination repair,the DNA double strand breaks site is digested to 3' single-stranded DNA,which is important for Rad51-mediated strand exchange.The SOSS1 complex,composed of SOSSA,SOSSB1,and SOSSC,recognizes single-stranded DNA(ssDNA)and participates in the DNA homologous recombination repair pathway.However,it is not clearly how SOSS1 is assembled and subsequently recognizes ssDNA.The crystal structure of the N-terminal half of SOSSA(SOSSAN),SOSSB1 and SOSSC showed that SOSSAN serves as a scaffold to bind to both SOSSB1 and SOSSC.The crystal structure of SOSSAN/B1 and SOSSAN/B1/C in complex with ssDNA showed that SOSSB1 is responsible for recognizing ssDNA with a length of up to nine nucleotides.These crystal structures provide insights into the molecular mechanism of SOSS1 assembly and its recognition for ssDNA.Integrator complex subunit 6(INTS6)is a tumor suppressor that interacts with SOSS1 through direct interaction with SOSSA.In response to the DNA damage signals,INTS6 relocates to the DNA damage sites along with SOSSA and SOSSB1.The second aim of this study is to illustrate the molecular basis of the SOSS1/INTS6 interaction and to reveal the potential role of INTS6 in the DNA damage repair pathway.