REVEALING THE MECHANISMS LINKING GENOME REPLICATION AND EPIGENOME MAINTENANCE

forthcoming

DNA replication is essential for transmitting genetic information across cell divisions. Beyond DNA duplication, eukaryotic DNA replication forks must coordinate diverse processes necessary for the genome integrity maintenance, preservation of chromatin structure, and inheritance of epigenetic information contained within chromatin. DNA replication forks must perform these diverse tasks in real-time across various chromatin states and physiological conditions. To achieve coordination of these processes, many factors play pleiotropic roles, simultaneously regulating DNA synthesis with epigenome maintenance. Furthermore, the leading and lagging strands of the fork are replicated by distinct molecular machineries. This DNA replication asymmetry imposes significant mechanistic constraints, and genome and epigenome maintenance must adapt to it. The two strands exhibit differences in mutation rates, DNA damage repair, the mechanisms of maintenance of epigenetic marks, and silencing of transposable elements. The lagging strand may contribute to (epi)genetic instability under pathological conditions, yet the underlying mechanisms remain largely unknown. Our goal is to reveal new mechanisms linking DNA replication, fork stability, and chromatin maintenance, ensuring accurate duplication of all layers of chromosomal information. Our specific aims are as follows: (1) Reveal how the accurate genome replication coordinates with transposable element silencing. (2) Investigate how epigenome maintenance factors coordinate at replication forks to ensure accurate replication of genetic and epigenetic information across chromosomes. (3) Systematically dissect how are chromatin maintenance mechanisms linked to the leading and lagging strand replication and identify novel factors with dual roles in DNA replication and (epi)genome maintenance. We will uncover new fundamental principles that regulate genome replication and epigenome inheritance, critical for development and diseases.