The MCM and RecQ Helicase Families: Ancient Roles in DNA Replication and Genomic Stability Lead to Distinct Roles in Human Disease

DNA helicases are currently organized into superfamilies based on their sequence structures and 3-D conformations. Within each superfamily, there are members that have further evolved for specialized functions [1]. There is conservation of RecQ proteins from bacteria to humans. Whereas bacteria have one RecQ helicase, humans have evolved at least five differ‐ ent proteins [2]. The RecQ members belong to the helicase Superfamily II, and as such have the characteristic Rec fold [1]. In this chapter, we will focus on RecQ family members WRN, BLM and RECQL4 (RecQ protein-like 4), which is also referred to in the literature as RECQ4. Eukaryotic and archaeal MCMs belong to the helicase Superfamily VI, and have the AAA+ (ATPases associated with diverse cellular activities) fold [1, 3, 4, 5]. Both Rec and AAA+ folds are based on the ancestral ASCE (additional strand conserved E) fold or an alpha-betaalpha domain necessary for nucleoside triphosphate binding and catalysis [1, 6, 7]. A ration‐ ale for comparison of the RecQ and MCM family members relates to the importance of their activities for genomic integrity. The WRN and BLM proteins as well as other members of the RecQ family are characterized by this feature [8]. Both WRN and BLM are involved in DNA repair and a role for WRN in telomere homeostasis in humans is well established [2, 9]. MCM2-7 proteins, along with cofactors, are thought to function as the eukaryotic replicative helicase [10]. MCM8 [11, 12] and MCM9 [13, 14] are more recently discovered and their roles are less well defined. Although data point to a role for MCM8 in DNA replication, that role may be specialized in higher organisms. In human cells, MCM10 is recruited to chromoso‐