PRIM1
Domain
The catalytic domain (residues 1-190 and 303-408) adopts a typical 'prim' fold structure formed by two three strand beta-sheets that line the inside of the lower and upper parts, each surrounded by alpha-helices on the outside (PubMed:24043831, PubMed:24239947). It comprises a highly conserved catalytic triad, a structural zinc-binding motif and the nucleotide-binding motifs. The Asp-109, Asp-111 and Asp-306 catalytic triad binds two Mn2+ or Mg2+ ions which activate for nucleophilic attack the 3'-hydroxyl of the growing RNA primer or of the first NTP bound at the initiation site (PubMed:24043831, PubMed:24239947, PubMed:25550159, PubMed:26975377). The nucleotide-binding motifs coordinate the phosphates, the ribose and the base of a NTP molecule (PubMed:24043831). The interaction between O2' of the initiating NTP and Asp-306 stabilizes the ribose during the di-nucleotide synthesis (PubMed:26975377). It is proposed that the first nucleotide binds to the elongation site, followed by binding to the initiation site of a second NTP, which will become the 5'-terminal nucleotide of the primer (PubMed:26975377).
Function
Catalytic subunit of the DNA primase complex and component of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex - primosome/replisome) which play an essential role in the initiation of DNA synthesis (PubMed:17893144, PubMed:24043831, PubMed:25550159, PubMed:26975377, PubMed:31479243, PubMed:33060134, PubMed:9268648, PubMed:9705292). During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1, an accessory subunit POLA2 and two primase subunits, the catalytic subunit PRIM1 and the regulatory subunit PRIM2) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1 (By similarity). The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands (PubMed:17893144). These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively (By similarity). In the primase complex, both subunits are necessary for the initial di-nucleotide formation, but the extension of the primer depends only on the catalytic subunit (PubMed:17893144). Synthesizes 9-mer RNA primers (also known as the 'unit length' RNA primers). Incorporates only ribonucleotides in the presence of ribo- and deoxy-nucleotide triphosphates (rNTPs, dNTPs) (PubMed:26975377). Requires template thymine or cytidine to start the RNA primer synthesis, with an adenine or guanine at its 5'-end (PubMed:25550159, PubMed:26975377). Binds single stranded DNA (By similarity).
Involvement in disease
Primordial dwarfism-immunodeficiency-lipodystrophy syndrome
PDIL
An autosomal recessive syndrome characterized by growth failure with in utero growth retardation and severe postnatal growth restriction, severe microcephaly, absence of subcutaneous fat, and significant haematological and immune dysfunction. Patients have hypo- or agammaglobulinemia, lymphopenia, anemia, and thrombocytopenia. Most affected individuals die in early childhood from either respiratory or gastrointestinal infections.
None
The disease is caused by variants affecting the gene represented in this entry.
Sequence Similarities
Belongs to the eukaryotic-type primase small subunit family.
Alternative names
DNA primase small subunit, DNA primase 49 kDa subunit, p49, PRIM1