PSF3

PSF3 Full Name

GINS complex subunit 3

PSF3 Introduction

PSF3, also known as GINS complex subunit 3 (GINS3), is a core component of the highly conserved GINS (Go-Ichi-Ni-San) complex, which plays an indispensable role in eukaryotic DNA replication. As part of the CMG helicase complex—comprising Cdc45, the MCM2–7 helicase, and GINS—PSF3 contributes directly to the unwinding of double-stranded DNA at replication forks, enabling accurate and efficient genome duplication. For researchers and drug developers working on proliferative diseases, a recurring challenge is identifying replication-specific vulnerabilities without broadly affecting normal cells; PSF3 stands out in this regard because of its central positioning at the replication fork. Structural and biochemical studies have demonstrated that PSF3 is required for the proper assembly and stability of the GINS complex, and even subtle perturbations can disrupt helicase activity. Notably, evolutionary evidence from archaeal systems shows that GINS interacts dynamically with replicative polymerases such as PolD, underscoring its conserved role as a replication platform across domains of life.

Functionally, PSF3 has emerged as more than a passive structural subunit and is now recognized as a multifunctional coordinator of replication progression and genome stability. Recent findings reveal that PSF3 is critically involved in maintaining replication fork integrity under stress conditions. For example, it can directly recruit DNA polymerase theta (Polθ) to stalled replication forks, facilitating microhomology-mediated end joining (TMEJ), a specialized DNA repair pathway that enables cells to tolerate replication-associated DNA damage. This mechanism is particularly relevant in cells experiencing high replication stress, where fork collapse and double-strand breaks are frequent. Loss-of-function or truncation mutations in PSF3—especially within its C-terminal domain—impair this recruitment process, leading to accumulation of DNA damage and reduced cell survival. In parallel, studies in model organisms and pathogens have shown that reduced expression of PSF3 destabilizes replication forks and alters the transcriptional landscape of replication-associated genes, reinforcing its role as a guardian of replication fidelity.

Clinically, dysregulation or mutation of PSF3 is increasingly linked to both rare developmental disorders and cancer biology, making it a compelling therapeutic and diagnostic target. Hypomorphic variants of GINS3, such as D24G or D24N, have been identified in patients with Meier-Gorlin syndrome, a primordial dwarfism disorder characterized by impaired cell proliferation. These variants reduce protein stability and hinder proper GINS complex assembly, ultimately delaying S-phase progression and compromising DNA replication efficiency. On the other end of the disease spectrum, PSF3 is frequently upregulated in rapidly proliferating cancers, including hematological malignancies such as FLT3-mutant acute myeloid leukemia (AML). In these contexts, tumor cells exploit PSF3-mediated recruitment of Polθ to survive replication stress, suggesting that targeting the PSF3–Polθ axis could selectively sensitize cancer cells to DNA damage. Altogether, these insights position PSF3 at the intersection of replication control, DNA repair, and disease progression—addressing a critical unmet need for precise molecular targets in both developmental disorders and oncology.

Alternate Names for PSF3

GINS complex subunit 3; GINS3; PSF3 homolog: FLJ13912; GINS complex subunit 3 (Psf3 homolog); OTTHUMP00000164722

• 1.McQuaid ME, et al.; Hypomorphic GINS3 variants alter DNA replication and cause Meier-Gorlin syndrome. JCI Insight. 2022, 7(10):e155648.
  2.Salomane N, et al.; The impact of Iso-mukaadial acetate on Plasmodium falciparum transcriptional gene regulation. Sci Rep. 2025, 15(1):42381.