The genetic information (i.e., genome) of a human cell is encoded in strands of DNA. Each time a cell divides, the genome must be accurately replicated for transfer to a daughter cell.  DNA replication occurs during S-phase of the cell cycle and relies on high-fidelity, i.e. “replicative,” DNA polymerases that read template DNA strands and synthesize their complementary DNA. Additional “core” proteins and enzymes are also involved and the basic mechanism of human DNA replication has been deciphered. However, it is unknown how faithful replication of genomic DNA is achieved within a human cell.  For example, the majority of proteins and enzymes implicated in human DNA replication are dynamically modified by chemical and protein moieties in vivo.  The functional role and regulation of many of these modifications is unknown.  Furthermore, genomic DNA is continuously damaged by reactive metabolites and environmental mutagens and it is unclear how these damages are accommodated without compromising the fidelity of DNA replication.  Understanding the mechanisms by which faithful replication of genomic DNA occurs within human cells is critical to identifying and deciphering dysfunctions that lead to DNA replication catastrophes, such as mutations and genomic DNA re-arrangements, both of which are hallmarks of cancer. The goal of the Hedglin Lab is to decipher how efficient and faithful replication of the human genome is achieved within the highly-complex, dynamic, and reactive cellular environment.  To do so, we employ a multi-disciplinary, collaborative approach, combining biophysical, biochemical, and molecular and cellular biology techniques to; 1) identify cellular factors involved in various aspects of human DNA replication and; 2) re-constitute human DNA replication in various biological scenarios and at various levels of complexity.