SHPRHHLTF

SHPRHHLTF is a term used to describe the functional cooperation between two human DNA damage response proteins, SHPRH and HLTF. Both proteins are considered vertebrate homologs of the yeast Rad5 pathway and are implicated in post-replication repair and replication fork protection. In human cells, SHPRH and HLTF are associated with chromatin and participate in pathways that mitigate DNA damage during replication.

The primary role attributed to SHPRHHLTF is the promotion of PCNA polyubiquitination on lysine 63 (K63-linked), a modification that directs cells toward error-free lesion bypass via template switching rather than mutagenic translesion synthesis. SHPRH and HLTF can function as E3 ubiquitin ligases and are believed to act in a coordinated manner to recruit and organize ubiquitination machinery at stalled replication forks, often engaging with ubiquitin-conjugating enzymes such as UBE2N and UBE2V2.

Localization and regulation of the SHPRHHLTF axis depend on replication stress signals, DNA lesions, and interactions with PCNA. The two proteins may form a functional complex or operate in a parallel, compensatory fashion to ensure fork stability, fork restart, and the continuation of genome replication under stress.

Clinical and evolutionary context indicates that the SHPRHHLTF pathway is conserved in vertebrates and contributes to genomic integrity. Disruption or altered expression of SHPRH or HLTF has been associated with increased genomic instability and has been observed in various cancers, highlighting the pathway’s potential relevance to cancer biology and therapy.

See also: PCNA ubiquitination, Rad5, SHPRH, HLTF.