HARPing on about the DNA damage response during replication

Abstract

In this issue of Genes & Development, four papers report that the annealing helicase HepA-related protein (HARP, also known as SMARCAL1 [SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1]) binds directly to the ssDNA-binding protein Replication protein A (RPA) and is recruited to sites of replicative stress. Knockdown of HARP results in hypersensitivity to multiple DNA-damaging agents and defects in fork stability or restart. These exciting insights reveal a key new player in the S-phase DNA damage response.

Figure 1.

Potential targets of HARP activity at the replication fork. (A) HARP may act to prevent certain events at a stalled fork, stabilizing this structure. For example, it may limit helicase-mediated DNA unwinding at stalled forks to prevent extensive accumulation of ssDNA that may disrupt a stable fork structure (i). Precocious dissociation of the DNA polymerases at unstable forks could also result in unwinding of the nascent strand on the leading (ii) and lagging (iii) strand, and HARP may suppress the formation of these structures. Such unwinding could lead to flap formation and unwanted fork regression or aberrant homologous recombination. HARP could also prevent bubble formation behind the fork at genomic regions that are not yet packaged into chromatin and are inherently unstable, such as A-T-rich regions (iv). (B) Alternatively, after fork stalling, HARP may promote fork regression (left) or certain fork configurations required for lesion bypass (bottom right), but it could also act during a recombination-mediated fork restart event such as break-induced replication (top right).