BLM’s balancing act and the involvement of FANCJ in DNA repair

Figures & data

Table 1. Properties of the BLM and FANCJ DNA helicases.

Property	BLM	FANCJ	References
Helicase family	RecQ^a	Fe-S^b	^a[2], ^b[118,119]
Helicase directionality	3′ – 5′^a	5′ – 3′^b	^a [120], ^b[86]
DNA substrate specificity	Forked duplex^a, fixed D-loops^b, branch migratable 3-stranded structures^c, HJ^c, G4^d, double HJ^e, stalled/regressed replication forks^f, 5′-flap^g, 3′-overhang^h, DNA triplex^i	Forked duplex^j, fixed D-loops^j, G4^k, 5′-flap^j, 5′-overhang^l, DNA triplex^m	^a[121], ^b[122], ^c[13,121], ^d[13,67,68,121], ^e[14,123], ^f[123,124], ^g[48,125],^h[67,120], ^i[13], ^j[62], ^k[65,66,126], ^l[62], ^m[50]
Key protein partners	RPA^a, Top 3⍺^b, FEN1^c, RAD51^d, EXO-1^e, DNA2^f, BRCA1^g, FANCJ^h	RPA^i, TopBP1^j, MLH1^k, BRCA1^l, BLM^m	^a[127,128], ^b[14,129,130], ^c[125,131], ^d[132], ^e[15,133], ^f[15], ^g[51], ^h[38], ^i[45], ^j[134], ^k[59,135], ^l[30], ^m[38]
Proposed cellular biochemical activities	Double HJ dissolution^a, anti-recombinase^b, Fork regression^c, G4 resolution^d, DNA end-resection^e, RAD51 displacement^f	G4 resolution^g, RAD51 displacement^h	^a[14,123], ^b[1,13,14,26,48,49,136], ^c[123,124], ^d[13, 67,68,121], ^e[15,16], ^f[48], ^g[65,66,126], ^h[50]

Figure 1. Models depicting the recruitment of BLM, FANCJ and other DNA repair proteins to double-strand breaks. A, Homologous recombination repair. Early recruitment: Early responders including the MRN complex recruit to the DSB and activate ATM during S or G2 phases of the cell cycle. 1) ATM is activated by autophosphorylation which in-turn can amplify MRN-mediated signaling. MRN with its protein partner CTIP begin resection at the DSB, thereby initiating DSB repair by HR. 2) BLM is recruited to the DSB along with BRCA1 and FANCJ. It is unclear whether FANCJ and BRCA1 form a complex in solution before recruitment to the DSB or interact at the DSB. The interaction between FANCJ-BRCA1 and BLM may potentiate DSB repair by the HR pathway. 3) The short DNA overhangs created by the MRE11 nuclease of the MRN complex are stabilized by RPA. Late recruitment: Long 5ʹ strand resection occurs through the BLM-DNA2 or EXO1 pathway. FANCJ may functionally interact with BLM and MRE11 leading to the formation of RPA nucleated stable 3ʹ ssDNA. 1) The long RPA filament is replaced by RAD51 and this replacement is facilitated by BRCA2. Both BLM and FANCJ can negatively regulate HR by inhibiting RAD51 interaction with ssDNA filaments. Further, BLM’s retention at the DNA is aided by ubiquitylation, which is important for interaction of NBS1 with the MRN complex. B, Non-homologous end-joining. Early recruitment: Early responders including ATM and the MRN complex recruit to the DSB and set up a cascade for NHEJ during any phase of the cell cycle. 1) Upon detection of DSBs, ATM becomes phosphorylated and in turn phosphorylates other proteins functioning later in NHEJ. 2) The recruitment of DNA-PKcs followed by KU 70/80 complex at DSBs displaces MRN complex and initiates NHEJ. 3) BLM and potentially FANCJ may be recruited at this stage. Late recruitment: Whether BLM and FANCJ interact to modulate NHEJ is an important area of investigation. 1) BLM regulates the recruitment of the repair protein XRCC4 which enhances the joining activity of LIG4.

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